Compounds For Use In Treatment Of Mucositis

ABSTRACT

The present invention provides methods for treating and/or preventing mucostitis with one or more compounds, or pharmaceutically acceptable salts thereof, disclosed herein, or compositions comprising the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. provisional application Ser.No. 61/486,455 filed May 16, 2011, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention is directed, in part, to methods of treatingand/or preventing mucostitis with one or more compounds, orpharmaceutically acceptable salts thereof, disclosed herein, orcompositions comprising the same.

BACKGROUND OF THE INVENTION

Oral ulcerative mucositis is a common, painful, dose-limiting toxicityof chemotherapy and radiation therapy for cancer (Sonis, Nat. Rev.Cancer, 2004, 4, 277-284; Keefe et al., Cancer, 2007, 109, 820-831;Belim et al., Support Care Cancer, 2000, 8, 33-39; and Parulekar et al.,Oral Oncol., 1998, 34, 63-71). The disorder is characterized bybreakdown of the oral mucosa and results in the formation of ulcerativelesions. It can significantly affect nutritional intake, mouth care, andquality of life (Lalla et al., Dent. Clin. North Am., 2005, 49, 167-184;and Duncan et al., Head Neck, 2005, 27, 421-428). The ulcerations thataccompany mucositis are frequent portals of entry for oral bacteriaoften leading to sepsis or bacteremia. For patients receiving high-dosechemotherapy prior to hematopoietic cell transplantation, oral mucositishas been reported to be the single most debilitating complication oftransplantation (Belim et al., Support Care Cancer, 2000, 8, 33-39).Infections associated with the oral mucositis lesions can causelife-threatening systemic sepsis during periods of immunosuppression(Rapoport et al., J. Clin. Oncol., 1999, 17, 2446-2453). Mucositisresults in increased hospital stays and re-admission rates, and canresult in interruptions or early cessation of treatment regimens (Picoet al., The Oncologist, 1998, 3, 446-451; and Elting et al., Cancer,2003, 98, 1531-1539). The prevalence of mucositis is variable anddependent on the disease and type of treatment being used. Moderate tosevere mucositis occurs in virtually all patients who receive radiationtherapy for tumors of the head and neck. Among patients who are treatedwith induction therapy for leukemia or with many of the conditioningregimens for bone marrow transplant, is not unusual for more thanthree-quarters of patients to develop moderate to severe mucositis.(Belim et al., Support Care Cancer, 2000, 8, 33-39). Annually, nearly60,000 patients receive a diagnosis of head and neck cancer (Jemal etal., CA Cancer J. Clin., 2002, 52, 23-47) and severe mucositis occurs inup to 92% of these treated patients (Parulekar et al., Oral Oncol.,1998, 34, 63-71; Sonis et al., Cancer, 85, 2103-2113). Even in regimensconsidered to be low risk for development of mucosal toxicity, whereincidence rates may range between 10-15%, the large numbers of patientsreceiving chemotherapy translates to a significant number of patientswho experience mucositis (Rubenstein et al., Cancer, 2004, 100,2026-2046). In addition to quality of life issues, there is asubstantial impact of oral mucositis on medical care resources andcosts, estimated to be $17,000 per patient, which are related toincreased hospitalization stays, medical treatments and medications(Nonzee et al., Cancer, 2008, 113, 1446-1452).

Originally, it was believed that mucositis associated with chemotherapyor radiation treatment was a result of direct cytotoxicity on the basalepithelial cells of the alimentary tract believed to be particularlyvulnerable because of their high turnover rate. It has become clear thatthe pathobiology of mucositis is more complex and involves interactionsbetween the epithelial and the underlying layers and components of themucosa including fibroblasts, endothelium and extracellular matrix1.Five inter-related stages have been described for the pathobiologyassociated with oral mucositis and appear to be similar betweenchemotherapy and radiation-induced lesions. An initiation phase ischaracterized by DNA damage, reactive oxygen species generation andbasal epithelial cell death. These events lead to primary activation ofvarious transcription factors and signal transduction pathways,including NF-κB and p53. NF-kB activation results in the production ofinflammatory cytokines including tumor necrosis factor (TNF),interleukin-1β (IL-1β), interleukin-6 (IL-6) and other genes that affectmucosal integrity (Sonis, Nat. Rev. Cancer, 2004, 4, 277-284; and Sonis,Crit. Rev. Oral Biol. Med., 2002, 13, 380-390). These factors andcytokines have been identified in the mucosa and blood of patientsexperiencing mucositis during cancer treatments (Hall et al., Exp.Hematol., 1995, 23, 1256-1260; and Ferra et al., Haematologica, 1998,83, 1082-1087). The primary response is amplified through positivefeedback loops activating additional pro-inflammatory mediators andtransduction pathways such as cyclo-oxygenase-2 (COX-2) andmitogen-activated protein kinase signaling (e.g., p38). Together, thesepro-inflammatory responses initiate an inflammatory cascade leading toactivation of matrix metalloproteinases, including MMP-1 and MMP-3, thatcause further tissue damage (Tadashi, Modern Rheumatol., 2006, 16,197-205). Ulceration then develops which damages the mucosal epitheliumand creates portals for bacterial entry and colonization. This is theclinically-important stage where patients experience significant painand debilitation. It is likely that the bacterial membrane and cell wallcomponents, lipopolysaccharides (LPS) and lipoteichoic acid (LTA),interact with invading macrophages further stimulating the release ofpro-inflammatory cytokines and tissue damage (Sonis, Oral Oncol., 1998,34, 39-43). In severe cases, there is a risk that the bacteria canspread systemically through the underlying vasculature causingbacteremia and sepsis. Finally, healing occurs via signaling from theextracellular matrix resulting in re-epithelialization and restorationof normal mucosal integrity.

Based upon the robust population of bacteria, fungi and viruses in theoral cavity, numerous studies have concluded that the oral microflora,although not a significant factor in the primary etiology of mucositismay influence the course of the disease (Sonis, Oral Oncol., 2009, 45,1015-1020). There is a high degree of similarity between the oralmicroflora of hamsters and humans, and in a hamster model of mucositisthe increase in bacterial load in the ulcer lagged behind thedevelopment of the mucositis (Sonis, Oral Oncol., 2009, 45, 1015-1020).These findings do not support a primary role for bacterial numbers indriving mucositis but rather are consistent with the ulcer being afavorable environment for bacterial colonization that exacerbates theinitial pathology and increases the risk of subsequent bacteremia, feverand serious infection and sepsis. Although anti-bacterial andanti-fungal strategies have proven to be ineffective in treating oralmucositis (Donnelly et al., Lancet Infect. Dis., 2003, 3, 405-412; andEl-Sayed et al., J. Clin. Oncol., 2002, 20, 3956-3963), they will likelybe of value in controlling fever and infection aspects of the disease atits later stages.

Despite its frequency, severity and impact on patients' ability totolerate cancer treatment, there is currently only one approvedpharmaceutical for the prevention or treatment for oral mucositis.Palifermin (Kepivance®, recombinant human keratinocyte growth factor-1)was approved for a mucositis indication in patients with hematologicmalignancies receiving stem cell transplants. Its efficacy may berelated to mitogenic effects on mucosal epithelium and/or alteration ofcytokine profiles, including down-regulation of TNF (Logan et al.,Cancer Treatment Rev., 2007, 33, 448-460). Palifermin is not widely useddue in part to concerns on the potential impact of a growth factor onantineoplastic treatment. Therefore, the care for mucositis is largelypalliative. Available agents include topical analgesics (lidocaine),barrier devices (GelClair), or rinses (Caphosol). Systemic analgesicsare used for symptom control and antibiotics are used to controlsecondary infections, and mucositis-related bacteremias and sepsis.Another agent proposed to be used for treatment of mucositis is NX002,which is a peptide derived from AMP-18 (see, U.S. Pat. Nos. 7,910,543and 7,629,317).

Antimicrobial peptides (AMPs) isolated from organisms across thephylogenetic spectrum form part of the innate immune system, and serveas the first line of defense against microbial infection in many species(Brogden, Nat. Rev. Microbiol., 2005, 3, 238-250; and Zasloff Nature,2002, 415, 389-395). They are typically small (12-80 amino acids)cationic amphiphiles that provide protection against a wide variety ofpathogenic organisms. Despite the large diversity observed in AMPs, theygenerally adopt highly amphiphilic topologies in which the hydrophilicand hydrophobic side chains segregate into distinctly opposing regionsor faces of the molecule. It is generally believed that this amphiphilictopology is essential for insertion into and disruption of the membraneleading to microbe death (Zasloff, Nature, 2002, 415, 389-395). AMPshave remained an effective weapon against bacterial infection overevolutionary time indicating that their mechanism of action thwartsbacterial responses that lead to resistance against toxic substances.This premise is supported by direct experimental data showing that noappreciable resistance to the action of the AMPs occurs after multipleserial passages of bacteria in the presence of sub-lethal concentrationsof the peptides (Gazit et al., Biochemistry, 1995, 34, 11479-11488; andPouny et al., Biochemistry, 1992, 31, 12416-12423).

The cytotoxic activity of the cationic and amphiphilic peptidesspecifically targets bacteria over mammalian cells. This specificity ismost likely related to fundamental differences between the two membranetypes; bacteria have a large proportion of negatively chargedphospholipid headgroups on their surface while the outer leaflet ofmammalian cells is composed mainly of neutral lipids (Zasloff, Nature,2002, 415, 389-395). Also, the presence of cholesterol in the animalcell membrane and other differences in lipid compositions with bacterialmembranes contribute to the selectivity of the AMPs (Yang et al., J. Am.Chem. Soc., 2007, 129, 12141-12147).

Given their very broad specificity, amphiphilic AMPs appear to be idealtherapeutic agents. However, significant pharmaceutical issues,including poor tissue distribution, systemic toxicity, and difficultyand expense of manufacturing, have severely hampered their clinicalprogress. A series of non-peptidic mimics of the AMPs that have distinctadvantages over peptides for pharmaceutical uses have been developed.The goal of the synthetic approach was to capture the structural andbiological properties of AMPs within the framework of inexpensiveoligomers (Scott et al., Curr. Opin. Biotechnol., 2008, 19, 620-627; andTew et al., ACCC, 2009, 43, 30-39). It was reasoned that small syntheticoligomers that adopt amphiphilic secondary structures while exhibitingpotent and selective antimicrobial activity would be less expensive toproduce, have better tissue distribution, and be much easier tofine-tune structurally to improve activity and minimize toxicity.

Clearly, there is a high medical need for the development of safe andeffective therapies that can prevent or significantly lessen theclinical course of ulcerative mucositis without negatively influencingthe cancer therapy. The apparent multifactorial pathogenesis of oralmucositis suggests that a therapeutic agent that possesses dualanti-inflammatory and antimicrobial activities may be highly effectivein treating the disease.

SUMMARY OF THE INVENTION

The present invention provides methods of treating and/or preventingmucositis in a mammal comprising administering to the mammal in needthereof a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: X is O or S; R₁is C₁-C₉ straight or branched chain alkyl, optionally substituted withone or more —NH₂ or —NH—C(═NH)NH₂; Y is a bond or a carbonyl; Z is abond or a carbonyl; R₂ is hydrogen or C₁-C₉ straight or branched chainalkyl optionally substituted with one or more —NH₂ or —NH—C(═NH)NH₂; orR₂ is —X—R₁; R₃ is methylene or

wherein the methylene is substituted with C₁-C₉ straight or branchedchain alkyl, wherein the C₁-C₉ straight or branched chain alkyl isoptionally substituted with one or more —NH₂ or —NH—C(═NH)NH₂; n is2-10; and m is 1 or 2.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula II:

or a pharmaceutically acceptable salt thereof, wherein: X is O or S; Yis O or S; R₁ is H or —C(═O)-A, where A is C₁-C₉ straight or branchedalkyl optionally substituted with one or more —NH₂, —N(CH₃)₂ or—NH—C(═NH)NH₂; R₂ is C₁-C₉ straight or branched alkyl optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂; R₃ isC₁-C₉ straight or branched alkyl optionally substituted with one or more—NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂; and R₄ is H, —B, or —C(═O)—O—B, where Bis C₁-C₉ straight or branched alkyl.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula III:

or a pharmaceutically acceptable salt thereof, wherein: each A is,independently, —C═O, —C═S, or CH₂; each D is, independently, O or S;each R¹ is, independently, hydrogen, C₁₋₃alkyl, C₁₋₃alkoxy, halo, orhaloC₁₋₃alkyl; each R² is, independently, hydrogen, C₁₋₃alkyl,C₁₋₃alkoxy, halo, or haloC₁₋₃alkyl; each R³ is, independently, hydrogen,C₁₋₄alkyl, C₁₋₄alkoxy, halo, or haloC₁₋₄alkyl; and each R⁴ is,independently, hydrogen, C₁₋₃alkyl, C₁₋₃alkoxy, halo, or haloC₁₋₃alkyl.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula IV:

or a pharmaceutically acceptable salt thereof, wherein: n=1 to 10; X isO or S; Y is O or S; Z is a bond, C₁-C₉ straight or branched alkyl, or a1,4-cyclohexyl; R₁ is NH₂ or NH-A, where A is C₁-C₉ straight or branchedalkyl, where A is optionally substituted with —NH₂, —N(CH₃)₂ or—NH—C(═NH)NH₂; R₂ is C₁-C₉ straight or branched alkyl, where R₂ isoptionally substituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂;R₃ is C₁-C₉ straight or branched alkyl, where R₃ is optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂; R₄ is H or

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula V:

or a pharmaceutically acceptable salt thereof, wherein: n is 2-8; X is abond, O or —O—CH₂—C(═O)—O—; R₁ is -A or —O-A, where A is C₁-C₉ straightor branched alkyl; and R₂ is C₁-C₉ straight or branched alkyl, where R₂is optionally substituted with one or more —NH₂, —N(CH₃)₂, or—NH—C(═NH)NH₂.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula VI:

or a pharmaceutically acceptable salt thereof, wherein: n is 2 to 10; R₁is H or

R₂ is C₁-C₉ straight or branched alkyl, where R₂ is optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂; R₃ isC₁-C₉ straight or branched alkyl, where R₂ is optionally substitutedwith one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂; R₄ is OH, NH₂ or

where A is OH or NH₂.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula VII:

or a pharmaceutically acceptable salt thereof, wherein: X is C(R⁷)C(R⁸),C(═O), N(R⁹), O, S, S(═O), or S(═O)₂; R⁷, R⁸, and R⁹ are, independently,H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH, CF₃, or aromatic group; R¹ and R²are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH,haloC₁-C₈alkyl, or CN; R³ and R⁴ are, independently, carbocycle(R⁵)(R⁶);each R⁵ and each R⁶ are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy,halo, OH, CF₃, aromatic group, heterocycle, or the free base or saltform of —(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 8.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula VIII:

or a pharmaceutically acceptable salt thereof, wherein: X is O or S;each Y is, independently, O, S, or N; each R¹ is, independently, H, 5-or 6-membered heterocycle, or the free base or salt form of—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; or each R¹ is, independently, together with Y a5- or 6-membered heterocycle; each R² is, independently, H, CF₃,C(CH₃)₃, halo, or OH; and each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula IX:

Q-X—Z—X-Q  IX

or a pharmaceutically acceptable salt thereof, wherein: Z is

or phenyl; each Q is, independently,

or —C(═O)—(CH₂)_(b)—NH—C(═NH)—NH₂, where each b is, independently, 1 to4; each X is, independently, O, S, or N; each R¹ is, independently, H,CF₃, C(CH₃)₃, halo, or OH; each R³ is, independently, H, —NH—R², —(CH₂),NH₂, —NH₂, —NH—(CH₂)_(w)—NH₂, or

where each r is, independently, 1 or 2, each w is, independently, 1 to3, and each y is, independently, 1 or 2; each R² is, independently, H,or the free base or salt form of (CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; each R⁴is, independently, H, —NH—C(═O)—(CH₂)_(p)—NH—C(═NH)—NH₂ or

where each p is, independently, 1 to 6, and each q is, independently, 1or 2; and each R⁵ is, independently, H or CF₃.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula X:

or a pharmaceutically acceptable salt thereof, wherein: G is

each X is, independently, O or S; each R¹ is, independently,

or the free base or salt form of —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; each R²is, independently, H, C₁-C₈alkyl, or the free base or salt form of—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; each R^(3 is, independently, H, CF) ₃, C(CH₃)₃,halo, or OH; and each R⁴ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XI:

or a pharmaceutically acceptable salt thereof, wherein: each X is,independently, O, S, or S(═O)₂; each R¹ is, independently,—(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴,where each n is, independently, 1 to 4, and each R⁴ is, independently,H, C₁-C₃alkyl, or —(CH₂)_(p)—NH₂, where each p is, independently, 1 or2; each R² is, independently, H, halo, CF₃, or C(CH₃)₃; and each V² isH, and each V¹ is, independently, —N—C(═O)—R³, where each R³ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 4; or each V¹ is H and each V² is,independently, —S—R⁵, where each R⁵ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XII:

or a pharmaceutically acceptable salt thereof, wherein: each Y is,independently, O, S, or NH; each R¹ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; andeach R² is, independently, H, halo, CF₃, or C(CH₃)₃.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XIII:

or a pharmaceutically acceptable salt thereof, wherein: each R¹ is,independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH, CF₃, or CN; each R²is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where eachn is, independently, 1 to 4.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XIV:

or a pharmaceutically acceptable salt thereof, wherein: D is

each B is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4,

and each X is, independently, O or S.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XV:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H or C₁₋₁₀alkyl; R² is H or C₁₋₁₀ alkyl; and m is 1 or 2.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XVI:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H or C₁₋₈alkyl; and R² is H or C₁₋₈ alkyl.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XVII:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H or C₁₋₈alkyl; and R² is H or C₁₋₈ alkyl.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XVIII:

R¹-[-X-A₁-Y—X-A₂-Y-]_(m)-R²  XVIII

or a pharmaceutically acceptable salt thereof, wherein: each X is,independently, NR⁸, —N(R⁸)N(R⁸)—, O, or S; each Y is, independently,C═O, C═S, O═S═O, —C(═O)C(═O)—, or —CR^(a)R^(b)—; R^(a) and R^(b) areeach, independently, hydrogen, a PL group, or an NPL group; each R⁸ is,independently, hydrogen or alkyl; A₁ and A₂ are each, independently,optionally substituted arylene or optionally substituted heteroarylene,wherein A₁ and A₂ are, independently, optionally substituted with one ormore PL group(s), one or more NPL group(s), or a combination of one ormore PL group(s) and one or more NPL group(s); or each A₁ is,independently, optionally substituted arylene or optionally substitutedheteroarylene, and each A₂ is a C₃ to C₈ cycloalkyl or —(CH₂)_(q)—,wherein q is 1 to 7, wherein A₁ and A₂ are, independently, optionallysubstituted with one or more PL group(s), one or more NPL group(s), or acombination of one or more PL group(s) and one or more NPL group(s); oreach A₂ is optionally substituted arylene or optionally substitutedheteroarylene, and each A₁ is a C₃ to C₈ cycloalkyl or —(CH₂)_(q)—,wherein q is 1 to 7, wherein A₁ and A₂ are each, independently,optionally substituted with one or more PL group(s), one or more NPLgroup(s), or a combination of one or more PL group(s) and one or moreNPL group(s); R¹ is hydrogen, a PL group, or an NPL group, and R² is—X-A₁-Y—R¹¹, wherein R¹¹ is hydrogen, a PL group, or an NPL group; or R¹and R² are each, independently, hydrogen, a PL group, or an NPL group;or R¹ and R² together are a single bond; or R¹ is —Y-A₂-X—R¹², whereinR¹² is hydrogen, a PL group, or an NPL group, and R² is hydrogen, a PLgroup, or an NPL group; each NPL group is, independently, —B(OR⁴)₂ or—(NR^(3′))_(q1NPL)—U^(NPL)-LK^(NPL)—(NR^(3″))_(q2NPL)—R^(4′), wherein:R³, R^(3′), and R^(3″) are each, independently, hydrogen, alkyl, oralkoxy; R⁴ and R^(4′) are each, independently, hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, or heteroaryl, wherein each of the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more substitutents, wherein each substituent is,independently, alkyl, halo, or haloalkyl; each U^(NPL) is,independently, absent or O, S, S(═O), S(═O)₂, NR³, —C(═O)—, —C(═O)—NR³—,—C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —S—C═N—, or —C(═O)—NR³—O—,wherein groups with two chemically nonequivalent termini can adopt bothpossible orientations; each LK^(NPL) is, independently, —(CH₂)_(pNPL)—or C₂₋₈ alkenylenyl, wherein each of the —(CH₂)_(pNPL) and C₂₋₈alkenylenyl is optionally substituted with one or more substituents,wherein each substituent is, independently, amino, hydroxyl, aminoalkyl,hydroxylalkyl, or alkyl; each pNPL is, independently, an integer from 0to 8; q1NPL and q2NPL are each, independently, 0, 1, or 2; each PL groupis, independently, halo, hydroxyethoxymethyl, methoxyethoxymethyl,polyoxyethylene, or—(NR^(5′))_(q1NPL)—U^(PL)-LK^(PL)—(NR^(5″))_(q2PL)—V, wherein: R⁵,R^(5′), and R^(5″) are each, independently, hydrogen, alkyl, or alkoxy;each U^(PL) is, independently, absent or O, S, S(═O), S(═O)₂, NR⁵,—C(═O)—, —C(═O)—NR⁵—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—,—C(═N—N(R⁵)₂)—, —C(═NR⁵)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—,—S—C═N—, or —C(═O)—NR⁵—O—, wherein groups with two chemicallynonequivalent termini can adopt either of the two possible orientations;each V is, independently, nitro, cyano, amino, halo, hydroxy, alkoxy,alkylthio, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to5, —C(═O)NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—C(═O)NH(CH₂)_(p)NHC(═NH)NH₂ wherein p is 1 to 5,—C(═O)NH(CH₂)_(p)NHC(═O)NH₂ wherein p is 1 to 5, —NHC(═O)-alkyl,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, ureido, carbamoyl,—C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH,S(═O)₂OH, NR^(d)R^(e), semicarbazone, aryl, cycloalkyl,heterocycloalkyl, or heteroaryl, wherein each of the aryl and cycloalkylis substituted with one or more substitutents, wherein each of theheterocycloalkyl and heteroaryl is optionally substituted with one ormore substituents, and wherein each of the substituents for the aryl,cycloalkyl, heterocycloalkyl, and heteroaryl is, independently, nitro,cyano, amino, halo, hydroxy, alkoxy, alkylthio, alkylamino,dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂,diazamino, amidino, guanidino, ureido, carbamoyl, —C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH,NR^(d)R^(e), semicarbazone, aminosulfonyl, aminoalkoxy, aminoalkythio,lower acylamino, or benzyloxycarbonyl; each R^(c) is, independently,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl, each optionally substitutedby one or more substitutents, wherein each substituent is,independently, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl;R^(d) and R^(e) are, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl,wherein each of the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionallysubstituted by OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, orheterocycloalkyl; or R^(d) and R^(e) together with the N atom to whichthey are attached form a 4-, 5-, 6-, 7-, or 8-membered heterocycloalkyl;each LK^(PL) is, independently, —(CH₂)_(pPL)— or C₂₋₈ alkenylenyl,wherein each of the —(CH₂)_(pNPL)— and C₂₋₈ alkenylenyl is optionallysubstituted with one or more substituents, wherein each substituent is,independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;each pPL is, independently, an integer from 0-8; q1PL and q2PL are each,independently, 0, 1, or 2; and m is an integer from 1 to about 20.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XIX:

R¹-[-X-A₁-X—Y-A₂-Y-]_(m)-R²  XIX

Or a pharmaceutically acceptable salt thereof, wherein: each X is,independently, NR⁸, O, S, —N(R⁸)N(R⁸)—, —N(R⁸)—(N═N)—, —(N═N)—N(R⁸)—,—C(R⁷R^(7′))NR⁸—, —C(R⁷R^(7′))O—, or —C(R⁷R^(7′))S—; each Y is,independently, C═O, C═S, O═S═O, —C(═O)C(═O)—, C(R⁶R^(6′))C═O, orC(R⁶R^(6′))C═S; each R⁸ is, independently, hydrogen or alkyl; each R⁷and each R^(7′) are, independently, hydrogen or alkyl; or R⁷ and R^(7′)together form —(CH₂)_(p)—, wherein p is 4 to 8; each R⁶ and each R^(6′)are, independently, hydrogen or alkyl; or R⁶ and R^(6′) together form(CH₂)₂NR¹²(CH₂)₂—, wherein R¹² is hydrogen, —C(═N)CH₃, or —C(═NH)—NH₂;A₁ and A₂ are each, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein A₁ and A₂ are each,independently, optionally substituted with one or more PL group(s), oneor more NPL group(s), or a combination of one or more PL group(s) andone or more NPL group(s); or each A₂ is, independently, optionallysubstituted arylene or optionally substituted heteroarylene, and each A₁is, independently, optionally substituted C₃ to C₈ cycloalkyl, whereinA₁ and A₂ are each, independently, optionally substituted with one ormore PL group(s), one or more NPL group(s), or a combination of one ormore PL group(s) and one or more NPL group(s); R¹ is hydrogen, a PLgroup, or an NPL group, and R² is —X-A₁-X—R¹, wherein A₁ is as definedabove and is optionally substituted with one or more PL group(s), one ormore NPL group(s), or a combination of one or more PL group(s) and oneor more NPL group(s); or R¹ is hydrogen, a PL group, or an NPL group,and R² is —X-A′-X—R¹, wherein A′ is C₃ to C₈ cycloalkyl, aryl, orheteroaryl and is optionally substituted with one or more PL group(s),one or more NPL group(s), or a combination of one or more PL group(s)and one or more NPL group(s); or R¹ is —Y-A₂-Y—R², and each R² is,independently, hydrogen, a PL group, or an NPL group; or R¹ is —Y-A¹ andR² is —X-A′, wherein each A′ is, independently, C₃ to C₈ cycloalkyl,aryl, or heteroaryl and is optionally substituted with one or more PLgroup(s), one or more NPL group(s), or a combination of one or more PLgroup(s) and one or more NPL group(s); or R¹ and R² are, independently,a PL group or an NPL group; or R¹ and R² together form a single bond;each NPL is, independently, —B(OR⁴)₂ or—(NR^(3′))_(q1NPL)—U^(NPL)-LK^(NPL)—(NR^(3″))_(q2NPL)—R^(4′), wherein:R³, R^(3′), and R^(3″) are each, independently, hydrogen, alkyl, oralkoxy; R⁴ and R^(4′) are each, independently, hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, and heteroaryl, wherein each of the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more alkyl or halo groups; each U^(NPL) is,independently, absent or O, S, S(═O), S(═O)₂, NR³, —C(═O)—, —C(═O)—NR³—,—C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —S—C═N—, or —C(═O)—NR³—O—,wherein groups with two chemically nonequivalent termini can adopt bothpossible orientations; each LK^(NPL) is, independently, —(CH₂)_(pNPL)—or C₂₋₈ alkenylenyl, wherein each of the —(CH₂)_(pNPL)— and C₂₋₈alkenylenyl is optionally substituted with one or more substituents,wherein each substituent is, independently, amino, hydroxyl, aminoalkyl,hydroxylalkyl, or alkyl; each pNPL is, independently, an integer from 0to 8; q1NPL and q2NPL are each, independently, 0, 1, or 2; each PL is,independently, halo, hydroxyethoxymethyl, methoxyethoxymethyl,polyoxyethylene, or —(NR⁵)_(q1PL)—U^(PL)-LK^(PL)—(NR^(5′))_(q2PL)—V,wherein: R⁵, R^(5′), and R^(5″) are each, independently, hydrogen,alkyl, and alkoxy; each U^(PL) is, independently, absent or O, S, S(═O),S(═O)₂, NR⁵, —C(═O)—, —C(═O)—NR⁵—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—,—N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—, —C(═O)O—, —C(═O)S—, —C(═S)—,—O—P(═O)₂O—, —S—C═N—, or —C(═O)—NR⁵—O—, wherein groups with twochemically nonequivalent termini can adopt either of the two possibleorientations; each V is, independently, nitro, cyano, amino, halo,hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂wherein p is 1 to 5, —C(═O)NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—C(═O)NH(CH₂)_(p)NHC(═NH)NH₂ wherein p is 1 to 5,—C(═O)NH(CH₂)_(p)NHC(═O)NH₂ wherein p is 1 to 5, —NHC(═O)-alkyl,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, ureido, carbamoyl,—C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH,S(═O)₂OH, NR^(d)R^(e), semicarbazone, aryl, cycloalkyl,heterocycloalkyl, or heteroaryl, wherein each of the aryl and cycloalkylis substituted with one or more substitutents, wherein each of theheterocycloalkyl, and heteroaryl is optionally substituted with one ormore substituents, and wherein each of the substituents for the aryl,cycloalkyl, heterocycloalkyl, and heteroaryl is, independently, nitro,cyano, amino, halo, hydroxy, alkoxy, alkylthio, alkylamino,dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂,diazamino, amidino, guanidino, ureido, carbamoyl, —C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH,NR^(d)R^(e), semicarbazone, aminosulfonyl, aminoalkoxy, aminoalkythio,lower acylamino, or benzyloxycarbonyl; each LK^(PL) is, independently,—(CH₂)_(pPL)— or C₂₋₈ alkenylenyl, wherein each of the —(CH₂)_(pNPL)—and C₂₋₈ alkenylenyl is optionally substituted with one or moresubstituents, wherein each substituent is, independently, amino,hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl; each pPL is,independently, an integer from 0 to 8; q1PL and q2PL are each,independently, 0, 1, or 2; and m is an integer from 1 to about 20.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XX:

or a pharmaceutically acceptable salt thereof, wherein: each X is,independently, NR⁸; each Y is C═O; each R⁸ is, independently, hydrogenor alkyl; each A₂ is optionally substituted arylene or optionallysubstituted heteroarylene, and each A₁ is —(CH₂)_(q)—, wherein q is 1 to7, wherein A₁ and A₂ are each, independently, optionally substitutedwith one or more PL group(s), one or more NPL group(s), or a combinationof one or more PL group(s) and one or more NPL group(s); R² and R^(2a)are each, independently, hydrogen, a PL group, an NPL group or—X-A₁-Y—R¹¹, wherein R¹¹ is hydrogen, a PL group, or an NPL group; L¹ isC₁₋₁₀alkylene optionally substituted with one or more substitutents,wherein each substituent is, independently, alkyl, halo, haloalkyl,aminoalkyl, hydroxylalkyl, V, or —(CH₂)_(pPL)—V, wherein pPL is aninteger from 1 to 5; each NPL group is, independently, —B(OR⁴)₂ or—(NR³)_(q1NPL)—U^(NPL)-LK^(NPL)—(NR^(3″))_(q2NPL)—R^(4′), wherein: R³,R^(3′), and R^(3″) are each, independently, hydrogen, alkyl, or alkoxy;R⁴ and R^(4′) are each, independently, hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, or heteroaryl, wherein each of the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more substitutents, wherein each substituent is,independently, alkyl, halo, or haloalkyl; each U^(NPL) is,independently, absent or O, S, S(═O), S(═O)₂, NR³, —C(═O)—, —C(═O)—NR³—,—C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —S—C═N—, or —C(═O)—NR³—O—,wherein groups with two chemically nonequivalent termini can adopt bothpossible orientations; each LK^(NPL) is, independently, —(CH₂)_(pNPL)—and C₂₋₈ alkenylenyl, wherein each of the —(CH₂)_(pNPL) and C₂₋₈alkenylenyl is optionally substituted with one or more substituents,wherein each substituent is, independently, amino, hydroxyl, aminoalkyl,hydroxylalkyl, or alkyl; each pNPL is, independently, an integer from 0to 8; q1NPL and q2NPL are each, independently, 0, 1, or 2; each PL groupis, independently, halo, hydroxyethoxymethyl, methoxyethoxymethyl,polyoxyethylene, or —(NR^(5′))_(q1PL)—U^(PL)-LK^(PL)—(NR^(5″))_(q2PL)—V,wherein: R⁵, R^(5′), and R^(5″) are each, independently, hydrogen,alkyl, or alkoxy; each U^(PL) is, independently, absent or O, S, S(═O),S(═O)₂, NR⁵, —C(═O)—, —C(═O)—NR⁵—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—,—N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—, —C(═O)O—, —C(═O)S—, —C(═S)—,—O—P(═O)₂O—, —S—C═N—, or —C(═O)—NR⁵—O—, wherein groups with twochemically nonequivalent termini can adopt either of the two possibleorientations; each V is, independently, nitro, cyano, amino, halo,hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂wherein p is 1 to 5, C(═O)NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—C(═O)NH(CH₂)_(p)NHC(═NH)NH₂ wherein p is 1 to 5,—C(═O)NH(CH₂)_(p)NHC(═O)NH₂ wherein p is 1 to 5, —NHC(═O)-alkyl,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, ureido, carbamoyl,—C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH,S(═O)₂OH, NR^(d)R^(e), semicarbazone, aryl, cycloalkyl,heterocycloalkyl, or heteroaryl, wherein each of the aryl and cycloalkylis substituted with one or more substitutents, wherein each of theheterocycloalkyl and heteroaryl is optionally substituted with one ormore substituents, and wherein each of the substituents for the aryl,cycloalkyl, heterocycloalkyl, and heteroaryl is, independently, nitro,cyano, amino, halo, hydroxy, alkoxy, alkylthio, alkylamino,dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂,diazamino, amidino, guanidino, ureido, carbamoyl, —C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH,NR^(d)R^(e), semicarbazone, aminosulfonyl, aminoalkoxy, aminoalkythio,lower acylamino, or benzyloxycarbonyl; each R^(c) is, independently,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl, each optionally substitutedby one or more substitutents, wherein each substituent is,independently, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl;R^(d) and R^(e) are, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl,wherein each of the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionallysubstituted by OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, orheterocycloalkyl; or R^(d) and R^(e) together with the N atom to whichthey are attached form a 4-, 5-, 6-, 7-, or 8-membered heterocycloalkyl;each LK^(PL) is, independently, —(CH₂)_(pNPL)— or C₂₋₈ alkenylenyl,wherein each of the —(CH₂)_(pNPL)— and C₂₋₈ alkenylenyl is optionallysubstituted with one or more substituents, wherein each substituent is,independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;each pPL is, independently, an integer from 0 to 8; q1PL and q2PL areeach, independently, 0, 1, or 2; m11 is an integer from 1 to about 20;and m12 is an integer from 1 to about 20.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XXI:

R¹-[-X-A₁-Y—X-A₂-Y-]_(m13)-X-L¹-Y-[-X-A₁-Y—X-A₂-Y-]_(m14)-R²  XXI

or a pharmaceutically acceptable salt thereof, wherein: each X is,independently, NR⁸; each Y is C═O; each R⁸ is, independently, hydrogenor alkyl; each A₂ is optionally substituted arylene or optionallysubstituted heteroarylene, and each A₁ is —(CH₂)_(q)—, wherein q is 1 to7, wherein A₁ and A₂ are each, independently, optionally substitutedwith one or more PL group(s), one or more NPL group(s), or a combinationof one or more PL group(s) and one or more NPL group(s); R¹ is hydrogen,a PL group, or an NPL group, and R² is —X-A₁-Y—R¹¹, wherein R¹¹ ishydrogen, a PL group, or an NPL group; or R¹ and R² are each,independently, hydrogen, a PL group, or an NPL group; or R¹ and R²together are a single bond; or R¹ is —Y-A₂-X—R¹², wherein R¹² ishydrogen, a PL group, or an NPL group, and R² is hydrogen, a PL group,or an NPL group; L¹ is C₁₋₁₀alkylene optionally substituted with one ormore substitutents, wherein each substituent is, independently, alkyl,halo, haloalkyl, aminoalkyl, hydroxylalkyl, V, or —(CH₂)_(pPL)—V whereinpPL is an integer from 1 to 5; each V is, independently, hydroxy, amino,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—C(═O)NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —C(═O)NH(CH₂)_(p)NHC(═NH)NH₂wherein p is to 5, —C(═O)NH(CH₂)_(p)NHC(═O)NH₂ wherein p is 1 to 5,—NHC(═O)-alkyl, —N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, carbamoyl,—C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH,S(═O)₂OH, NR^(d)R^(e), a substituted aryl group, heterocycloalkyl, orheteroaryl, wherein each of the heterocycloalkyl and heteroaryl isoptionally substituted with one more substituents, wherein eachsubstituent is, independently, amino, halo, cyano, nitro, hydroxy,—NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, amidino, guanidino,aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, orbenzyloxycarbonyl; and wherein the substituted aryl group is substitutedwith one more substituents, wherein each substituent is, independently,amino, halo, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl, aminoalkoxy,aminoalkythio, lower acylamino, or benzyloxycarbonyl; each NPL group is,independently, —B(OR⁴)₂ or—(NR^(3′))_(q1NPL)—U^(NPL)-LK^(NPL)—(NR^(3″))_(q2NPL)—R^(4′), wherein:R³, R^(3′), and R^(3″) are each, independently, hydrogen, alkyl, oralkoxy; R⁴ and R^(4′) are each, independently, hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, or heteroaryl, wherein each of the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more substitutents, wherein each substituent is,independently, alkyl, halo, or haloalkyl; each U^(NPL) is,independently, absent or O, S, S(═O), S(═O)₂, NR³, —C(═O)—, —C(═O)—NR³—,C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —S—C═N—, or —C(═O)—NR³—O—,wherein groups with two chemically nonequivalent termini can adopt bothpossible orientations; each LK^(NPL) is, independently, —(CH₂)_(pNPL)—or C₂₋₈ alkenylenyl, wherein each of the —(CH₂)_(pNPL) and C₂₋₈alkenylenyl is optionally substituted with one or more substituents,wherein each substituent is, independently, amino, hydroxyl, aminoalkyl,hydroxylalkyl, or alkyl; each pNPL is, independently, an integer from 0to 8; q1NPL and q2NPL are each, independently, 0, 1, or 2; each PL groupis, independently, halo, hydroxyethoxymethyl, methoxyethoxymethyl,polyoxyethylene, or —(NR^(5′))_(q1PL)—U^(PL)-LK^(PL)—(NR^(5″))_(q2PL)—V,wherein: R⁵, R^(5′), and R^(5″) are each, independently, hydrogen,alkyl, or alkoxy; each U^(PL) is, independently, absent or O, S, S(═O),S(═O)₂, NR⁵, —C(═O)—, —C(═O)—NR⁵—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—,—N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—, —C(═O)O—, —C(═O)S—, —C(═S)—,—O—P(═O)₂O—, —S—C═N—, or —C(═O)—NR⁵—O—, wherein groups with twochemically nonequivalent termini can adopt either of the two possibleorientations; each R^(c) is, independently, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, orheterocycloalkylalkyl, each optionally substituted by one or moresubstitutents, wherein each substituent is, independently, OH, amino,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl, or heterocycloalkyl; R^(d) and R^(e) are,independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, wherein eachof the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted byOH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;or R^(d) and R^(e) together with the N atom to which they are attachedform a 4-, 5-, 6-, 7-, or 8-membered heterocycloalkyl; each LK^(PL) is,independently, —(CH₂)_(pPL)— or C₂₋₈ alkenylenyl, wherein each of the—(CH₂)_(pNPL)— and C₂₋₈ alkenylenyl is optionally substituted with oneor more substituents, wherein each substituent is, independently, amino,hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl; each pPL is,independently, an integer from 0 to 8; q1PL and q2PL are each,independently, 0, 1, or 2; m13 is an integer from 1 to about 10; and m14is an integer from 1 to about 10.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XXII:

R¹-[-X-A₁-X—Z—Y-A₂-Y—Z]_(m)—R²  XXII

or a pharmaceutically acceptable salt thereof, wherein: X is NR⁸,—NR⁸NR⁸—, C═O, or O; Y is NR⁸, —NR⁸NR⁸—, C═O, S, or O; R⁸ is hydrogen oralkyl; Z is C═O, C═S, O═S═O, —NR⁸NR⁸—, or —C(═O)C(═O)—; A₁ and A₂ are,independently, optionally substituted arylene or optionally substitutedheteroarylene, wherein A₁ and A₂ are, independently, optionallysubstituted with one or more polar (PL) group(s), one or more non-polar(NPL) group(s), or a combination of one or more polar (PL) group(s) andone or more non-polar (NPL) group(s); R¹ is (i) hydrogen, a polar group(PL), or a non-polar group (NPL), and R² is —X-A₁-X—R¹, wherein A₁ is asdefined above and is optionally substituted with one or more polar (PL)group(s), one or more non-polar (NPL) group(s), or a combination of oneor more polar (PL) group(s) and one or more non-polar (NPL) group(s); or(ii) hydrogen, a polar group (PL), or a non-polar group (NPL), and R² is—X-A₁-X—Z—Y-A₂-Y—R¹, wherein A₁ and A₂ are as defined above, and each ofwhich is optionally substituted with one or more polar (PL) group(s),one or more non-polar (NPL) group(s), or a combination of one or morepolar (PL) group(s) and one or more non-polar (NPL) group(s); or (iii)hydrogen, a polar group (PL), or a non-polar group (NPL), and R² is—X-A′-X—R¹, wherein A′ is aryl or heteroaryl and is optionallysubstituted with one or more polar (PL) group(s), one or more non-polar(NPL) group(s), or a combination of one or more polar (PL) group(s) andone or more non-polar (NPL) group(s); or (iv) hydrogen, a polar group(PL), or a non-polar group (NPL), and R² is —X-A₁-X—Z—Y-A′-Y—R¹, whereinA₁ is as defined above, A′ is aryl or heteroaryl, and each of A₁ and A′is optionally substituted with one or more polar (PL) group(s), one ormore non-polar (NPL) group(s), or a combination of one or more polar(PL) group(s) and one or more non-polar (NPL) group(s); or (v) —Z—Y-A¹and R² is hydrogen, a polar group (PL), or a non-polar group (NPL),wherein A″ is aryl or heteroaryl and is optionally substituted with oneor more polar (PL) group(s), one or more non-polar (NPL) group(s), or acombination of one or more polar (PL) group(s) and one or more non-polar(NPL) group(s); or (vi) —Z—Y-A′, and R² is —X-A″, wherein A′ and A″ are,independently, aryl or heteroaryl, and each of A and A″ is optionallysubstituted with one or more polar (PL) group(s), one or more non-polar(NPL) group(s), or a combination of one or more polar (PL) group(s) andone or more non-polar (NPL) group(s); or (vii) R¹ and R² are,independently, a polar group (PL) or a non-polar group (NPL); or (viii)R¹ and R² together form a single bond; NPL is a nonpolar groupindependently selected from —B(OR⁴)₂ and—(NR³)_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R^(4′), wherein:R³, R^(3′), and R^(3″) are, independently, selected from hydrogen,alkyl, and alkoxy; R⁴ and R^(4′) are, independently, selected fromhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, anyof which is optionally substituted with one or more alkyl or halogroups; U^(NPL) is absent or selected from O, S, S(═O), S(═O)₂, NR³,—C(═O)—, —C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—,—C(═NR³)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³⁰—, —R³S—,—S—C═N—, and —C(═O)—NR³—O—, wherein groups with two chemicallynonequivalent termini can adopt both possible orientations; the—(CH₂)_(pNPL)— alkylene chain is optionally substituted with one or moreamino or hydroxy groups, or is unsaturated; pNPL is to 8; q1NPL andq2NPL are, independently, 0, 1, or 2; PL is a polar group selected fromhalo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5′))_(q2PL)—V, wherein: R⁵,R^(5′), and R^(5″) are, independently, selected from hydrogen, alkyl,and alkoxy; U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵,—C(═O)—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—,—C(═NR⁵)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—,—S—C═N—, and —C(═O)—NR⁵—O—, wherein groups with two chemicallynonequivalent termini can adopt both possible orientations; V isselected from nitro, cyano, amino, hydroxy, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 4,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, guanyl, semicarbazone,aryl, heterocycle, and heteroaryl, any of which is optionallysubstituted with one or more of amino, halo, cyano, nitro, hydroxy,—NH(CH₂)_(p)NH₂ wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, amidino, guanidino,guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, orbenzyloxycarbonyl; the —(CH₂)_(pPL)— alkylene chain is optionallysubstituted with one or more amino or hydroxy groups, or is unsaturated;pPL is 0 to 8; q1PL and q2PL are, independently, 0, 1, or 2; and m is 1to about 20.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XXIII:

R¹-[-A₁-W-A₂-W-]_(m)-R²  XXIII

or a pharmaceutically acceptable salt thereof, wherein: A₁ and A₂ are,independently, optionally substituted arylene or optionally substitutedheteroarylene, wherein: (i) A₁ and A₂ are, independently, optionallysubstituted with one or more polar (PL) group(s), one or more non-polar(NPL) group(s), or a combination of one or more polar (PL) group(s) andone or more non-polar (NPL) group(s); or (ii) one of A₁ or A₂ is asdefined above and is optionally substituted with one or more polar (PL)group(s), one or more non-polar (NPL) group(s), or a combination of oneor more polar (PL) group(s) and one or more non-polar (NPL) group(s);and the other of A₁ or A₂ is the group —C≡C(CH₂)_(p)C≡C—, wherein p is 0to 8, and the —(CH₂)_(p)— alkylene chain is optionally substituted withone or more amino or hydroxyl groups; W is absent, or represents —CH₂—,—CH₂—CH₂—, —CH═CH—, or —C≡C—; R¹ is (i) hydrogen, a polar group (PL), ora non-polar group (NPL), and R² is -A₁-R¹, wherein A₁ is as definedabove and is optionally substituted with one or more polar (PL)group(s), one or more non-polar (NPL) group(s), or a combination of oneor more polar (PL) group(s) and one or more non-polar (NPL) group(s); or(ii) hydrogen, a polar group (PL), or a non-polar group (NPL), and R² is-A₁-W-A₂-R¹, wherein each of A₁ and A₂ is as defined above and isoptionally substituted with one or more polar (PL) group(s), one or morenon-polar (NPL) group(s), or a combination of one or more polar (PL)group(s) and one or more non-polar (NPL) group(s); or (iii) A′-W— and R²is -A₁-W-A′, wherein A′ is aryl or heteroaryl, either of which isoptionally substituted with one or more polar (PL) group(s), one or morenon-polar (NPL) group(s), or a combination of one or more polar (PL)group(s) and one or more non-polar (NPL) group(s); or (iv) A′-W— and R²is -A′, wherein A′ is aryl or heteroaryl, either of which is optionallysubstituted with one or more polar (PL) group(s), one or more non-polar(NPL) groups(s), or a combination of one or more polar (PL) group(s) andone or more non-polar (NPL) group(s); or (iv) R¹ and R² together form asingle bond; NPL is a nonpolar group independently selected from—B(OR⁴)₂ or—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R⁴, wherein:R³, R^(3′), and R^(3″) are, independently, selected from hydrogen,alkyl, and alkoxy; R⁴ is selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionallysubstituted with one or more alkyl or halo groups; U^(NPL) is absent orselected from O, S, S(═O), S(═O)₂, NR³, —(C═O)—, —(C═O)—N═N—NR³—,—(C═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—, —C(═O)O—,—C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³⁰—, —R³S—, —S—C═N— and —(C═O)—NR³—O—,wherein groups with two chemically nonequivalent termini can adopt bothpossible orientations; the —(CH₂)_(pNPL)— alkylene chain is optionallysubstituted with one or more alkyl, amino or hydroxyl groups, or thealkylene chain is unsaturated; pNPL is 0 to 8; q1NPL and q2NPL are,independently, 0 to 2; PL is a polar group selected from halo,hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5′))_(q2PL)—V, wherein: R⁵,R^(5′), and R^(5″) are, independently, selected from hydrogen, alkyl,and alkoxy; U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵,—(C═O)—, —(C═O)—N═N—NR⁵—, —(C═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—,—C(═NR⁵)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—,—S—C═N—, and —(C═O)—NR⁵—O—, wherein groups with two chemicallynonequivalent termini can adopt both possible orientations; V isselected from nitro, cyano, amino, hydroxyl, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂, —N(CH₂CH₂NH₂)₂, diazamino,amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle, andheteroaryl, any of which is optionally substituted with one or more ofamino, halo, cyano, nitro, hydroxyl, —NH(CH₂)_(p)NH₂, —N(CH₂CH₂NH₂)₂,amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio,lower acylamino, or benzyloxycarbonyl; the —(CH₂)_(pPL)— alkylene chainis optionally substituted with one or more amino or hydroxyl groups, orthe alkylene chain is unsaturated; pPL is 0 to 8; q1PL and q2PL are,independently, 0 to 2; and m is 1 to about 25.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XXIV:

R¹—X-A₁-X—Y-A₂-Y—X-A₁-X—R²  XXIV

or a pharmaceutically acceptable salt thereof, wherein: X is NR⁸, O, S,or —N(R⁸)N(R⁸)—; Y is C═O, C═S, or O═S═O; R⁸ is hydrogen or alkyl; A₁and A₂ are, independently, optionally substituted arylene or optionallysubstituted heteroarylene, wherein A₁ and A₂ are, independently,optionally substituted with one or more polar (PL) group(s), one or morenon-polar (NPL) group(s), or a combination of one or more polar (PL)group(s) and one or more non-polar (NPL) group(s); R¹ is a polar group(PL) or a non-polar group (NPL); R² is R¹; NPL is a nonpolar groupindependently selected from —B(OR⁴)₂ and—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R^(4′),wherein: R³, R^(3′), and R^(3″) are, independently, selected fromhydrogen, alkyl, and alkoxy; R⁴ and R^(4′) are, independently, selectedfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, and heteroaryl, any of which is optionally substitutedwith one or more alkyl or halo groups; U^(NPL) is absent or selectedfrom O, S, S(═O), S(═O)₂, NR³, —C(═O)—, —C(═O)—N═N—NR³—,—C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—, —C(═O)O—,—C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³⁰—, —R³S—, —S—C═N—, and—C(═O)—NR³—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations; the —(CH₂)_(pNPL)— alkylene chainis optionally substituted with one or more amino or hydroxy groups, oris unsaturated; pNPL is 0 to 8; q1NPL and q2NPL are, independently, 0,1, or 2; PL is a polar group selected from halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, and—(NR⁵)_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5′))_(q2PL)—V, wherein: R⁵,R^(5′), and R^(5″) are, independently, selected from hydrogen, alkyl,and alkoxy; U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵,—C(═O)—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—,—C(═NR⁵)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—,—S—C═N—, and —C(═O)—NR⁵—O—, wherein groups with two chemicallynonequivalent termini can adopt both possible orientations; V isselected from nitro, cyano, amino, hydroxy, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 4,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, guanyl, semicarbazone,aryl, heterocycle and heteroaryl, any of which is optionally substitutedwith one or more of amino, halo, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, amidino, guanidino, guanyl,aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, orbenzyloxycarbonyl; the —(CH₂)_(pPL)— alkylene chain is optionallysubstituted with one or more amino or hydroxy groups, or is unsaturated;pPL is 0 to 8; and q1PL and q2PL are, independently, 0, 1, or 2.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XXV:

A-(B)_(n1)-(D)_(m1)-H  XXV

or a pharmaceutically acceptable salt thereof, wherein: A is the residueof a chain transfer agent; B is —[CH₂—C(R¹¹)(B₁₁)]—, wherein B₁₁ is—X₁₁—Y₁₁—Z₁₁, wherein X₁₁ is carbonyl (—C(═O)—) or optionallysubstituted C₁₋₆ alkylene; or X₁₁ is absent; Y₁₁ is O, NH, or optionallysubstituted C₁₋₆ alkylene; or Y₁₁ is absent; Z₁₁ is —Z_(11A)—Z_(11B),wherein Z_(11A) is alkylene, arylene, or heteroarylene, any of which isoptionally substituted; or Z_(11A) is absent; and Z_(11B) is -guanidino,-amidino, —N(R³)(R⁴), or —N⁺(R³)(R⁴)(R⁵), wherein R³, R⁴, and R⁵ are,independently, hydrogen, alkyl, aminoalkyl, aryl, heteroaryl,heterocyclic, or aralkyl; or Z₁₁ is pyridinium

or phosphonium

wherein R⁸¹, R⁹¹¹, R⁹²¹, and R⁹³¹ are, independently, hydrogen or alkyl;R¹¹ is hydrogen or C₁₋₄ alkyl; D is —[CH₂—C(R²¹)(D₂₁)]—, wherein D₂₁ is—X₂₁—Y₂₁—Z₂₁, wherein X₂₁ is carbonyl (—C(═O)—) or optionallysubstituted C₁₋₆ alkylene; or X₂₁ is absent; Y₂, is O, NH, or optionallysubstituted C₁₋₆ alkylene, or Y₂₁ is absent; Z₂₁ is alkyl, cycloalkyl,alkoxy, aryl, or aralkyl, any of which is optionally substituted; R²¹ ishydrogen or C₁₋₄ alkyl; m₁, the mole fraction of D, is about 0.1 toabout 0.9; and n₁, the mole fraction of B, is 1-m₁; wherein the compoundis a random copolymer of B and D, and wherein the copolymer has a degreeof polymerization of about 5 to about 50.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of

In some embodiments, the compounds described herein, or compositionscomprising the same, can be combined with other therapeutic agents, suchas palifermin, or compositions comprising the same for treatment and/orprevention of mucositis.

In some embodiments, the present methods for treating and/or preventingmucositis can be used in a patient who receives chemotherapy and/orradiation therapy for cancer. In some embodiments, the patient isreceiving or will be receiving high-dose chemotherapy prior tohematopoietic cell transplantation. In some embodiments, the patient isreceiving or will be receiving radiation therapy for tumors of the headand neck. In some embodiments, the patient is receiving or will bereceiving induction therapy for leukemia. In some embodiments, thepatient is receiving or will be receiving conditioning regimens for bonemarrow transplant. In some embodiments, the patient is experiencing orwill be experiencing basal epithelial cell death.

The present invention is also directed to use of the compounds andcompositions of the invention in the preparation of medicaments fortreating and/or preventing mucositis.

The present invention is also directed to use of the compounds andcompositions of the invention for treating and/or preventing mucositis.

DESCRIPTION OF EMBODIMENTS

Unless defined otherwise, all technical and scientific terms have thesame meaning as is commonly understood by one of ordinary skill in theart to which the embodiments disclosed belongs.

As used herein, the terms “comprising” (and any form of comprising, suchas “comprise”, “comprises”, and “comprised”), “having” (and any form ofhaving, such as “have” and “has”), “including” (and any form ofincluding, such as “includes” and “include”), or “containing” (and anyform of containing, such as “contains” and “contain”), are inclusive oropen-ended and do not exclude additional, un-recited elements or methodsteps.

As used herein, the terms “a” or “an” means “at least one” or “one ormore” unless the context clearly indicates otherwise.

As used herein, the term “about” means that the numerical value isapproximate and small variations would not significantly affect thepractice of the disclosed embodiments. Where a numerical limitation isused, unless indicated otherwise by the context, “about” means thenumerical value can vary by ±10% and remain within the scope of thedisclosed embodiments.

As used herein, the term “n-membered”, where n is an integer, typicallydescribes the number of ring-forming atoms in a moiety, where the numberof ring-forming atoms is n. For example, pyridine is an example of a6-membered heteroaryl ring and thiophene is an example of a 5-memberedheteroaryl ring.

As used herein, the term “alkyl” refers to a saturated hydrocarbon groupwhich is straight-chained or branched. An alkyl group can contain from 1to 20, from 2 to 20, from 1 to 10, from 1 to 8, from 1 to 6, from 1 to4, or from 1 to 3 carbon atoms. Examples of alkyl groups include, butare not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g.,n-pentyl, isopentyl, neopentyl), and the like.

As used herein, the term “alkylene” or “alkylenyl” refers to a divalentalkyl linking group. An example of an alkylene (or alkylenyl) ismethylene or methylenyl (—CH₂—).

As used herein, the term “alkenyl” refers to an alkyl group having oneor more double carbon-carbon bonds. Examples of alkenyl groups include,but are not limited to, ethenyl, propenyl, cyclohexenyl, and the like.

As used herein, the term “alkenylenyl” refers to a divalent linkingalkenyl group.

As used herein, the term “alkynyl” refers to an alkyl group having oneor more triple carbon-carbon bonds. Examples of alkynyl groups include,but are not limited to, ethynyl, propynyl, and the like.

As used herein, the term “alkynylenyl” refers to a divalent linkingalkynyl group.

As used herein, the term “haloalkyl” refers to an alkyl group having oneor more halogen substituents. Examples of haloalkyl groups include, butare not limited to, CF₃, C₂F₅, CHF₂, CCl₃, CHCl₂, C₂Cl₅, CH₂CF₃, and thelike.

As used herein, the term “aryl” refers to monocyclic or polycyclic(e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons. In someembodiments, aryl groups have from 6 to about 20 carbon atoms. In someembodiments, aryl groups have from 6 to 10 carbon atoms. Examples ofaryl groups include, but are not limited to, phenyl, naphthyl,anthracenyl, phenanthrenyl, indanyl, indenyl, and the like.

As used herein, the term “cycloalkyl” refers to non-aromatic cyclichydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups thatcontain up to 20 ring-forming carbon atoms. Cycloalkyl groups caninclude mono- or polycyclic ring systems such as fused ring systems,bridged ring systems, and spiro ring systems. In some embodiments,polycyclic ring systems include 2, 3, or 4 fused rings. A cycloalkylgroup can contain from 3 to about 15, from 3 to 10, from 3 to 8, from 3to 6, from 4 to 6, from 3 to 5, or from 5 to 6 ring-forming carbonatoms. Ring-forming carbon atoms of a cycloalkyl group can be optionallysubstituted by oxo or sulfido. Examples of cycloalkyl groups include,but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and thelike. Also included in the definition of cycloalkyl are moieties thathave one or more aromatic rings fused (having a bond in common with) tothe cycloalkyl ring, for example, benzo or thienyl derivatives ofpentane, pentene, hexane, and the like (e.g.,2,3-dihydro-1H-indene-1-yl, or 1H-inden-2(3H)-one-1-yl).

As used herein, the term “heteroaryl” refers to an aromatic heterocyclehaving up to ring-forming atoms and having at least one heteroatom ringmember (ring-forming atom) such as sulfur, oxygen, or nitrogen. In someembodiments, the heteroaryl group has at least one or more heteroatomring-forming atoms, each of which are, independently, sulfur, oxygen, ornitrogen. In some embodiments, the heteroaryl group has from 1 to about20 carbon atoms, from 1 to 5, from 1 to 4, from 1 to 3, or from 1 to 2,carbon atoms as ring-forming atoms. In some embodiments, the heteroarylgroup contains 3 to 14, 3 to 7, or 5 to 6 ring-forming atoms. In someembodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2heteroatoms. Heteroaryl groups include monocyclic and polycyclic (e.g.,having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groupsinclude, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl,imidazolyl, thiazolyl, indolyl (such as indol-3-yl), pyrryl, oxazolyl,benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl,triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl,benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and thelike.

As used herein, the term “heterocycloalkyl” refers to non-aromaticheterocycles having up to 20 ring-forming atoms including cyclizedalkyl, alkenyl, and alkynyl groups, where one or more of thering-forming carbon atoms is replaced by a heteroatom such as an O, N,or S atom. Heterocycloalkyl groups can be mono or polycyclic (e.g.,fused, bridged, or spiro systems). In some embodiments, theheterocycloalkyl group has from 1 to about 20 carbon atoms, or 3 toabout 20 carbon atoms. In some embodiments, the heterocycloalkyl groupcontains 3 to 14, 3 to 7, or 5 to 6 ring-forming atoms. In someembodiments, the heterocycloalkyl group has 1 to 4, 1 to 3, or 1 to 2heteroatoms. In some embodiments, the heterocycloalkyl group contains 0to 3 double bonds. In some embodiments, the heterocycloalkyl groupcontains 0 to 2 triple bonds. Examples of heterocycloalkyl groupsinclude, but are not limited to, morpholino, thiomorpholino,piperazinyl, tetrahydrofuranyl, tetrahydrothienyl,2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl,pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, imidazolidinyl, pyrrolidin-2-one-3-yl, andthe like. In addition, ring-forming carbon atoms and heteroatoms of aheterocycloalkyl group can be optionally substituted by oxo or sulfido.For example, a ring-forming S atom can be substituted by 1 or 2 oxo(form a S(O) or S(O)₂). For another example, a ring-forming C atom canbe substituted by oxo (form carbonyl). Also included in the definitionof heterocycloalkyl are moieties that have one or more aromatic ringsfused (having a bond in common with) to the nonaromatic heterocyclicring including, but not limited to, pyridinyl, thiophenyl, phthalimidyl,naphthalimidyl, and benzo derivatives of heterocycles such as indolene,isoindolene, 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-yl,5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl, isoindolin-1-one-3-yl,and 3,4-dihydroisoquinolin-1(2H)-one-3yl groups. Ring-forming carbonatoms and heteroatoms of the heterocycloalkyl group can be optionallysubstituted by oxo or sulfido.

As used herein, the term “halo” refers to halogen groups including, butnot limited to fluoro, chloro, bromo, and iodo.

As used herein, the term “alkoxy” refers to an —O-alkyl group. Examplesof alkoxy groups include, but are not limited to, methoxy, ethoxy,propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.

As used herein, the term “haloalkoxy” refers to an —O-haloalkyl group.An example of an haloalkoxy group is OCF₃.

As used herein, the term “alkylthio” refers to an —S-alkyl group. Anexample of an alkylthio group is —SCH₂CH₃.

As used herein, the term “arylalkyl” refers to a C₁₋₆ alkyl substitutedby aryl and “cycloalkylalkyl” refers to C₁₋₆ alkyl substituted bycycloalkyl.

As used herein, the term “heteroarylalkyl” refers to a C₁₋₆ alkyl groupsubstituted by a heteroaryl group, and “heterocycloalkylalkyl” refers toa C₁₋₆ alkyl substituted by heterocycloalkyl.

As used herein, the term “amino” refers to NH₂.

As used herein, the term “alkylamino” refers to an amino groupsubstituted by an alkyl group. An example of an alkylamino is —NHCH₂CH₃.

As used herein, the term “arylamino” refers to an amino groupsubstituted by an aryl group. An example of an alkylamino is—NH(phenyl).

As used herein, the term “aminoalkyl” refers to an alkyl groupsubstituted by an amino group. An example of an aminoalkyl is—CH₂CH₂NH₂.

As used herein, the term “aminosulfonyl” refers to —S(═O)₂NH₂.

As used herein, the term “aminoalkoxy” refers to an alkoxy groupsubstituted by an amino group. An example of an aminoalkoxy is—OCH₂CH₂NH₂.

As used herein, the term “aminoalkylthio” refers to an alkylthio groupsubstituted by an amino group. An example of an aminoalkylthio is—SCH₂CH₂NH₂.

As used herein, the term “amidino” refers to —C(═NH)NH₂.

As used herein, the term “acylamino” refers to an amino groupsubstituted by an acyl group (e.g., —O—C(═O)—H or —O—C(═O)-alkyl). Anexample of an acylamino is —NHC(═O)H or —NHC(═O)CH₃. The term “loweracylamino” refers to an amino group substituted by a loweracyl group(e.g., —O—C(═O)—H or —O—C(═O)—C₁₋₆alkyl). An example of a loweracylamino is —NHC(═O)H or —NHC(═O)CH₃.

As used herein, the term “carbamoyl” refers to —C(═O)—NH₂.

As used herein, the term “cyano” refers to —CN.

As used herein, the term “dialkylamino” refers to an amino groupsubstituted by two alkyl groups.

As used herein, the term “diazamino” refers to —N(NH₂)₂.

As used herein, the term “guanidino” refers to —NH(═NH)NH₂.

As used herein, the term “heteroarylamino” refers to an amino groupsubstituted by a heteroaryl group. An example of an alkylamino is—NH-(2-pyridyl).

As used herein, the term “hydroxyalkyl” or “hydroxylalkyl” refers to analkyl group substituted by a hydroxyl group. Examples of a hydroxylalkylinclude, but are not limited to, —CH₂OH and —CH₂CH₂OH.

As used herein, the term “nitro” refers to —NO₂.

As used herein, the term “semicarbazone” refers to ═NNHC(═O)NH₂.

As used herein, the term “ureido” refers to —NHC(═O)—NH₂.

As used herein, the phrase “optionally substituted” means thatsubstitution is optional and therefore includes both unsubstituted andsubstituted atoms and moieties. A “substituted” atom or moiety indicatesthat any hydrogen on the designated atom or moiety can be replaced witha selection from the indicated substituent group, provided that thenormal valency of the designated atom or moiety is not exceeded, andthat the substitution results in a stable compound. For example, if amethyl group is optionally substituted, then 3 hydrogen atoms on thecarbon atom can be replaced with substituent groups.

As used herein, the term, “compound” refers to all stereoisomers,tautomers, and isotopes of the compounds described in the presentinvention.

As used herein, the phrase “substantially isolated” refers to a compoundthat is at least partially or substantially separated from theenvironment in which it is formed or detected.

As used herein, the phrase “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith tissues of humans and animals.

As used herein, the term “animal” includes, but is not limited to,humans and non-human vertebrates such as wild, domestic and farmanimals.

As used herein, the term “contacting” refers to the bringing together ofan indicated moiety in an in vitro system or an in vivo system.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, such as mice,rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses,or primates, such as humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician.

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

For compounds of the invention in which a variable appears more thanonce, each variable can be a different moiety selected from the Markushgroup defining the variable. For example, where a structure is describedhaving two R groups that are simultaneously present on the samecompound, the two R groups can represent different moieties selectedfrom the Markush groups defined for R. In another example, when anoptionally multiple substituent is designated in the form:

then it is understood that substituent R can occur s number of times onthe ring, and R can be a different moiety at each occurrence. Further,in the above example, where the variable T¹ is defined to includehydrogens, such as when T¹ is CH₂, NH, etc., any floating substituentsuch as R in the above example, can replace a hydrogen of the T¹variable as well as a hydrogen in any other non-variable component ofthe ring.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended to be included within the scope of theinvention unless otherwise indicated. Compounds of the present inventionthat contain asymmetrically substituted carbon atoms can be isolated inoptically active or racemic forms. Methods of preparation of opticallyactive forms from optically active starting materials are known in theart, such as by resolution of racemic mixtures or by stereoselectivesynthesis. Many geometric isomers of olefins, C═N double bonds, and thelike can also be present in the compounds described herein, and all suchstable isomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention are alsoincluded within the scope of the invention and can be isolated as amixture of isomers or as separated isomeric forms. Where a compoundcapable of stereoisomerism or geometric isomerism is designated in itsstructure or name without reference to specific R/S or cis/transconfigurations, it is intended that all such isomers are contemplated.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art, including, for example, fractionalrecrystallizaion using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods include, but are not limited to,optically active acids, such as the D and L forms of tartaric acid,diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malicacid, lactic acid, and the various optically active camphorsulfonicacids such as β-camphorsulfonic acid. Other resolving agents suitablefor fractional crystallization methods include, but are not limited to,stereoisomerically pure forms of α-methylbenzylamine (e.g., S and Rforms, or diastereomerically pure forms), 2-phenylglycinol,norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine,1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures canalso be carried out by elution on a column packed with an opticallyactive resolving agent (e.g., dinitrobenzoylphenylglycine). Suitableelution solvent compositions can be determined by one skilled in theart.

Compounds of the invention may also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Examples ofprototropic tautomers include, but are not limited to, ketone-enolpairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acidpairs, enamine-imine pairs, and annular forms where a proton can occupytwo or more positions of a heterocyclic system including, but notlimited to, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H-and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention also include hydrates and solvates, as wellas anhydrous and non-solvated forms.

All compounds and pharmaceutically acceptable salts thereof can beprepared or be present together with other substances such as water andsolvents (e.g., hydrates and solvates) or can be isolated.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. Partial separation can include, for example,a composition enriched in the compound of the invention. Substantialseparation can include compositions containing at least about 50%, atleast about 60%, at least about 70%, at least about 80%, at least about90%, at least about 95%, at least about 97%, or at least about 99% byweight of the compound of the invention, or salt thereof. Methods forisolating compounds and their salts are routine in the art.

Compounds of the invention are intended to include compounds with stablestructures. As used herein, the phrases “stable compound” and “stablestructure” refer to a compound that is sufficiently robust to surviveisolation to a useful degree of purity from a reaction mixture, andformulation into an efficacious therapeutic agent.

The present invention also includes quaternary ammonium salts of thecompounds described herein, where the compounds have one or moretertiary amine moiety. As used herein, the phrase “quaternary ammoniumsalts” refers to derivatives of the disclosed compounds with one or moretertiary amine moieties wherein at least one of the tertiary aminemoieties in the parent compound is modified by converting the tertiaryamine moiety to a quaternary ammonium cation via alkylation (and thecations are balanced by anions such as Cl⁻, CH₃COO⁻, and CF₃COO⁻), forexample methylation or ethylation.

The present invention provides methods of treating and/or preventingmucositis in a mammal comprising administering to the mammal in needthereof a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof,wherein:

X is O or S;

R₁ is C₁-C₉ straight or branched chain alkyl, optionally substitutedwith one or more —NH₂ or —NH—C(═NH)NH₂;

Y is a bond or a carbonyl;

Z is a bond or a carbonyl;

R₂ is hydrogen or C₁-C₉ straight or branched chain alkyl optionallysubstituted with one or more —NH₂ or —NH—C(═NH)NH₂;

or R₂ is —X—R₁;

R₃ is methylene or

wherein the methylene is substituted with C₁-C₉ straight or branchedchain alkyl, wherein the C₁-C₉ straight or branched chain alkyl isoptionally substituted with one or more —NH₂ or —NH—C(═NH)NH₂;

n is 2-10; and

m is 1 or 2.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula II:

or a pharmaceutically acceptable salt thereof,wherein:

X is O or S;

Y is O or S;

R₁ is H or —C(═O)-A, where A is C₁-C₉ straight or branched alkyloptionally substituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂;

R₂ is C₁-C₉ straight or branched alkyl optionally substituted with oneor more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂;

R₃ is C₁-C₉ straight or branched alkyl optionally substituted with oneor more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂; and

R₄ is H, —B, or —C(═O)—O—B, where B is C₁-C₉ straight or branched alkyl.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound chosenfrom:

or a pharmaceutically acceptable salt thereof.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula III:

or a pharmaceutically acceptable salt thereof,wherein:

each A is, independently, —C═O, —C═S, or CH₂;

each D is, independently, O or S;

each R¹ is, independently, hydrogen, C₁₋₃alkyl, C₁₋₃alkoxy, halo, orhaloC₁₋₃alkyl;

each R² is, independently, hydrogen, C₁₋₃alkyl, C₁₋₃alkoxy, halo, orhaloC₁₋₃alkyl;

each R³ is, independently, hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, halo, orhaloC₁₋₄alkyl; and

each R⁴ is, independently, hydrogen, C₁₋₃alkyl, C₁₋₃alkoxy, halo, orhaloC₁₋₃alkyl.

In some embodiments, at least one A is —C═O. In some embodiments, each Ais —C═O.

In some embodiments, at least one D is O. In some embodiments, each D isO.

In some embodiments, each R¹ is, independently, hydrogen, methyl, ethyl,methoxy, ethoxy, halo, or haloC₁₋₃alkyl. In some embodiments, each R¹is, independently, hydrogen, methyl, methoxy, halo, or haloC₁₋₃alkyl. Insome embodiments, each R¹ is, independently, hydrogen, methyl, ormethoxy. In some embodiments, at least one R¹ is hydrogen. In someembodiments, each R¹ is hydrogen.

In some embodiments, each R² is, independently, hydrogen, methyl, ethyl,methoxy, ethoxy, halo, or haloC₁₋₃alkyl. In some embodiments, each R²is, independently, hydrogen, methyl, methoxy, or halo. In someembodiments, at least one R² is hydrogen. In some embodiments, each R²is hydrogen.

In some embodiments, each R³ is, independently, hydrogen, methyl, ethyl,methoxy, ethoxy, halo, or haloC₁₋₃alkyl. In some embodiments, each R³is, independently, methyl, methoxy, halo, or haloC₁₋₃alkyl. In someembodiments, each R³ is, independently, halo or haloC₁₋₃alkyl. In someembodiments, each R³ is, independently, haloC₁₋₃alkyl. In someembodiments, at least one R³ is trifluoromethyl. In some embodiments,each R³ is trifluoromethyl.

In some embodiments, each R⁴ is, independently, hydrogen, methyl, ethyl,methoxy, ethoxy, or haloC₁₋₃alkyl. In some embodiments, each R⁴ is,independently, hydrogen, methyl, methoxy, halo, or haloC₁₋₃alkyl. Insome embodiments, each R⁴ is, independently, hydrogen, methyl, methoxy,or halo. In some embodiments, at least one R⁴ is hydrogen. In someembodiments, each R⁴ is hydrogen.

In some embodiments, each A is, independently, —C═O or —C═S; each D is,independently, O or S; each R¹ is, independently, hydrogen, methyl,ethyl, methoxy, ethoxy, halo, halomethyl, or haloethyl; each R² is,independently, hydrogen, methyl, methoxy, halo, or halomethyl; each R³is, independently, C₁₋₃alkyl, C₁₋₃alkoxy, halo, or haloalkyl; and eachR⁴ is, independently, hydrogen, methyl, ethyl, methoxy, ethoxy, halo,halomethyl, or haloethyl.

In some embodiments, each A is, independently, —C═O or —C═S; each D is,independently, O or S; each R¹ is, independently, hydrogen, methyl,methoxy, halo, or halomethyl; each R² is, independently, hydrogen, halo,or halomethyl; each R³ is, independently, methyl, ethyl, methoxy,ethoxy, halo, halomethyl, or haloethyl; and each R⁴ is, independently,hydrogen, methyl, ethyl, methoxy, ethoxy, halo, halomethyl, orhaloethyl.

In some embodiments, each A is —C═O; each D is O; each R¹ is,independently, hydrogen, halo, or halomethyl; each R² is, independently,hydrogen or halo; each R³ is, independently, methyl, methoxy, halo, orhalomethyl; and each R⁴ is, independently, hydrogen, methyl, methoxy,halo, or halomethyl.

In some embodiments, each A is —C═O; each D is O; each R¹ is,independently, hydrogen or halo; each R² is, independently, hydrogen orhalo; each R³ is, independently, methyl, halo, or halomethyl; and eachR⁴ is, independently, hydrogen, methyl, halo, or halomethyl.

In some embodiments, each A is —C═O; each D is O; each R¹ is,independently, hydrogen or halo; each R² is, independently, hydrogen orhalo; each R³ is, independently, halo or halomethyl; and each R⁴ is,independently, hydrogen or halo.

In some embodiments, each A is —C═O; each D is O; each R¹ is,independently, hydrogen or halo; each R² is, independently, hydrogen orhalo; each R³ is, independently, methyl, halo, or halomethyl; and eachR⁴ is, independently, hydrogen, methyl, halo, or halomethyl.

In some embodiments, each A is —C═O; each D is O; each R¹ is,independently, hydrogen or halo; each R² is, independently, hydrogen orhalo; each R³ is, independently, halo or halomethyl; and each R⁴ is,independently, hydrogen, halo, or halomethyl.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula IV:

or a pharmaceutically acceptable salt thereof,wherein:

n=1 to 10;

X is O or S;

Y is O or S;

Z is a bond, C₁-C₉ straight or branched alkyl, or a 1,4-cyclohexyl;

R₁ is NH₂ or NH-A, where A is C₁-C₉ straight or branched alkyl, where Ais optionally substituted with —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂;

R₂ is C₁-C₉ straight or branched alkyl, where R₂ is optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂;

R₃ is C₁-C₉ straight or branched alkyl, where R₃ is optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂;

R₄ is H or

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound chosenfrom:

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula V:

or a pharmaceutically acceptable salt thereof,wherein:

n is 2-8;

X is a bond, O or —O—CH₂—C(═O)—O—,

R₁ is -A or —O-A, where A is C₁-C₉ straight or branched alkyl; and

R₂ is C₁-C₉ straight or branched alkyl, where R₂ is optionallysubstituted with one or more —NH₂, —N(CH₃)₂, or —NH—C(═NH)NH₂.

In some embodiments, n is 4-8.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound chosenfrom:

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula VI:

or a pharmaceutically acceptable salt thereof,wherein:

n is 2 to 10;

R₁ is H or

R₂ is C₁-C₉ straight or branched alkyl, where R₂ is optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂;

R₃ is C₁-C₉ straight or branched alkyl, where R₂ is optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂;

R₄ is OH, NH₂ or

where A is OH or NH₂.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound chosenfrom:

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula VII:

or a pharmaceutically acceptable salt thereof,wherein:

X is C(R⁷)C(R⁸), C(═O), N(R⁹), O, S, S(═O), or S(═O)₂;

R⁷, R⁸, and R⁹ are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH,CF₃, or aromatic group;

R¹ and R² are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH,haloC₁-C₈alkyl, or CN;

R³ and R⁴ are, independently, carbocycle(R⁵)(R⁶);

each R⁵ and each R⁶ are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy,halo, OH, CF₃, aromatic group, heterocycle, or the free base or saltform of —(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 8;

or a pharmaceutically acceptable salt thereof.

In some embodiments, X is N(R⁹), O, S, or S(═O)₂. In some embodiments, Xis NH, O, or S. In some embodiments, X is NH or S.

In some embodiments, R¹ and R² are, independently, H, C₁-C₃alkyl,C₁-C₃alkoxy, halo, OH, haloC₁-C₃alkyl, or CN. In some embodiments, R¹and R² are, independently, H, C₁-C₃alkyl, C₁-C₃alkoxy, halo, or OH. Insome embodiments, R¹ and R² are, independently, H, C₁-C₃alkyl, or halo.In some embodiments, R¹ and R² are H.

In some embodiments, R³ and R⁴ are, independently,

wherein:

each W, Y, and Z are, independently, C or N;

each A, D, and Q are, independently, C(R¹⁰)C(R¹¹), C(═O), N(R¹²), O, orS; and

each R¹⁰, R¹¹, and R¹² are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy,halo, OH, CF₃, or aromatic group. In some embodiments, R³ and R⁴ are,independently,

wherein each W, Y, and Z are, independently, C or N. In someembodiments, R³ and R⁴ are, independently,

wherein each W, Y, and Z are C; or each Y and Z are C and each W is N.

In some embodiments, each R⁵ is, independently, H, C₁-C₈alkyl,C₁-C₈alkoxy, halo, OH, CF₃, or the free base or salt form of—(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 8; and each R⁶ is, independently,heterocycle or the free base or salt form of —(CH₂)_(n)—NH₂,—(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to

In some embodiments, each R⁵ is, independently, H, C₁-C₃alkyl,C₁-C₃alkoxy, halo, OH, or CF₃; and each R⁶ is, independently,heterocycle or the free base or salt form of —(CH₂)_(n)—NH₂, where eachn is, independently, 1 to 8.

In some embodiments, each R⁵ is, independently, H, C₁-C₃alkyl, halo, orOH; and each R⁶ is, independently, heterocycle or the free base or saltform of —(CH₂)_(n)—NH₂, where each n is, independently, 1 to 4.

In some embodiments, each R⁵ is, independently, H, C₁-C₃alkyl, halo, orOH; and each R⁶ is, independently, 6-membered heterocycle or the freebase or salt form of —(CH₂)_(n)—NH₂, where each n is, independently, 1to 3.

In some embodiments, each R⁵ is, independently, H or halo; and each R⁶is piperazinyl or the free base or salt form of —(CH₂)_(n)—NH₂ whereeach n is, independently, 1 to 3.

In some embodiments, each R⁵ is piperazinyl; and each R⁶ is,independently, H, C₁-C₃alkyl, C₁-C₃alkoxy, halo, OH, or CF₃.

In some embodiments, each R⁵ is piperazinyl; and each R⁶ is H,C₁-C₃alkyl, halo, OH, or CF₃.

In some embodiments, X is NH, O, S, or S(═O)₂; R¹ and R² are H; R³ andR⁴ are, independently,

wherein: each W, Y, and Z are, independently, C or N; and each R⁵ andeach R⁶ are, independently, H, heterocycle, or the free base or saltform of —(CH₂)_(n)—NH₂, where each n is, independently, 1 to 3.

In some embodiments, X is NH, O, or S; R¹ and R² are H; R³ and R⁴ arewhere each Z and Y are C, and each W is N; or each W, Y, and Z are C;and each R⁵ is, independently, H or halo, and each R⁶ is piperazinyl orthe free base or salt form of —(CH₂)_(n)—NH₂, where each n is,independently, 1 to 3; or each R⁵ is piperazinyl, and each R⁶ is,independently, H, C₁-C₃alkyl, C₁-C₃alkoxy, halo, OH, or CF₃.

In some embodiments, X is NH, O, or S; R¹ and R² are H; R³ and R⁴ are

where each Z and Y are C, and each W is N; or each W, Y, and Z are C;and each R⁵ is H, and each R⁶ is piperazinyl or the free base or saltform of —(CH₂)_(n)—NH₂, where each n is, independently, 1 to 3; or eachR⁵ is piperazinyl; and each R⁶ is H.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound chosenfrom:

or pharmaceutically acceptable salt thereof.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula VIII:

or a pharmaceutically acceptable salt thereof,wherein:

X is O or S;

each Y is, independently, O, S, or N;

each R¹ is, independently, H, 5- or 6-membered heterocycle, or the freebase or salt form of —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, whereeach n is, independently, 1 to 4; or each R¹ is, independently, togetherwith Y a 5- or 6-membered heterocycle;

each R² is, independently, H, CF₃, C(CH₃)₃, halo, or OH; and

each R³ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4; or a pharmaceutically acceptablesalt thereof.

In some embodiments, X is O.

In some embodiments, Y is O or S.

In some embodiments, each R¹ is, independently, 5-membered heterocycleor the free base or salt form of —(CH₂)_(n)—NH₂, where each n is,independently, 1 to 4. In some embodiments, each R¹ is, independently,3-pyrrolyl or the free base or salt form of —(CH₂)_(n)—NH₂, where each nis, independently, 1 or 2.

In some embodiments, each R² is, independently, CF₃, C(CH₃)₃, or halo.

In some embodiments, each R³ is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4. In some embodiments, each R³ is—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 4.

In some embodiments, X is O or S; each Y is, independently, O or S; eachR¹ is, independently, 5-membered heterocycle, or the free base or saltform of —(CH₂)_(n)—NH₂, where each n is, independently, 1 to 4; each R²is, independently, CF₃ or C(CH₃)₃; and each R³ is, independently,—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4.

In some embodiments, X is O or S; each Y is O or S; each R¹ is5-membered heterocycle, or the free base or salt form of —(CH₂)_(n)—NH₂,where each n is 1 to 4; each R² is CF₃ or C(CH₃)₃; and each R³ is—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 to 4.

In some embodiments, X is O or S; each Y is O or S; each R¹ is3-pyrrolyl, or the free base or salt form of —(CH₂)_(n)—NH₂, where eachn is 2; each R² is CF₃ or C(CH₃)₃; and each R³ is—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 4.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound chosenfrom:

or pharmaceutically acceptable salt thereof.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula IX:

Q-X—Z-X-Q  IX

or a pharmaceutically acceptable salt thereof,wherein:

Z is

or phenyl;

each Q is, independently,

or —C(═O)—(CH₂)_(b)—NH—C(═NH)—NH₂, where each b is, independently, 1 to4;

each X is, independently, O, S, or N;

each R¹ is, independently, H, CF₃, C(CH₃)₃, halo, or OH;

each R³ is, independently, H, —NH—R², —(CH₂), NH₂, —NH₂,—NH—(CH₂)_(w)—NH₂, or

where each r is, independently, 1 or 2, each w is, independently, 1 to3, and each y is, independently, 1 or 2;

each R² is, independently, H, or the free base or salt form of—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4;

each R⁴ is, independently, H, —NH—C(═O)—(CH₂)_(p)—NH—C(═NH)—NH₂ or

where each p is, independently, 1 to 6, and each q is, independently, 1or 2; and

each R⁵ is, independently, H or CF₃;

or a pharmaceutically acceptable salt thereof.

In some embodiments, Z is

In some embodiments, each Q is, independently,

In some embodiments, each X is O.

In some embodiments, each R¹ is, independently, H, CF₃, or halo. In someembodiments, each R¹ is CF₃.

In some embodiments, each R³ is, independently, —NH—R².

In some embodiments, each R² is, independently, H, or the free base orsalt form of (CH₂)_(n)—NH₂, where each n is, independently, 1 to 4. Insome embodiments, each R² is, independently, the free base or salt formof —(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2. In someembodiments, each R² is the free base or salt form of —(CH₂)_(n)—NH₂,where each n is 2.

In some embodiments, each R⁴ and each R⁵ is H.

In some embodiments, Z is

each Q is, independently,

each X is O or S; each R¹ is, independently, CF₃, C(CH₃)₃, or halo; eachR³ is, independently, —NH—R²; each R² is, independently, H, or the freebase or salt form of —(CH₂)_(n)—NH₂, where each n is, independently, 1to 4; and each R⁴ and each R⁵ is H.

In some embodiments, Z is

each Q is, independently,

each X is O; each R¹ is CF₃, C(CH₃)₃, or halo; each R³ is,independently, —NH—R²; each R² is, independently, the free base or saltform of —(CH₂)_(n)—NH₂, where each n is or 2; and each R⁴ and each R⁵ isH.

In some embodiments, Z is

each Q is, independently,

each X is O; each R¹ is CF₃ or halo; each R³ is, independently, —NH—R²;each R² is the free base or salt form of —(CH₂)_(n)—NH₂, where each n is2; and each R⁴ and each R⁵ is H.

In some embodiments, Z is

each Q is, independently,

each X is, independently, O, or S; each R¹ is, independently, H, or CF₃;each R³ is H; each R⁴ is, independently, H or—NH—C(═O)—(CH₂)_(p)—NH—C(═NH)—NH₂, where each p is, independently, 3 or4; and each R⁵ is, independently, H or CF₃.

In some embodiments, Z is

each Q is, independently, —C(═O)—(CH₂)_(b)—NH—C(═NH)—NH₂, where each bis, independently, 3 or 4; and each X is N.

In some embodiments, Z is

each Q is, independently,

each X is O or S; each R¹ is, independently, H or CF₃; each R³ is,independently, —(CH₂)_(r)—NH₂, —NH₂, —NH—(CH₂)_(w)—NH₂, or

where each r is, independently, 1 or 2, each w is, independently, 1 to3, and each y is, independently, 1 or 2; each R⁴ is H; and each R⁵ is,independently, H or CF₃.

In some embodiments, Z is

or phenyl; each Q is, independently,

each X is, independently, O or S; each R¹ is, independently, H or CF₃;each R³ is H; each R⁴ is, independently,

where each q is, independently, 1 or 2; and each R⁵ is, independently, Hor CF₃.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound chosenfrom:

or a pharmaceutically acceptable salt thereof.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula X:

or a pharmaceutically acceptable salt thereof,wherein:

G is

each X is, independently, O or S;

each R¹ is, independently,

or the free base or salt form of —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4;

each R² is, independently, H, C₁-C₈alkyl, or the free base or salt formof —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4;

each R³ is, independently, H, CF₃, C(CH₃)₃, halo, or OH; and

each R⁴ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4.

In some embodiments, G is

and each X is S.

In some embodiments, each R¹ is, independently, the free base or saltform of —(CH₂)_(n)—NH₂, where each n is, independently, 1 to 4. In someembodiments, each R¹ is, independently, the free base or salt form of—(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2. In someembodiments, each R¹ is the free base or salt form of —(CH₂)_(n)—NH₂,where each n is 2.

In some embodiments, each R² is, independently, C₁-C₃alkyl or the freebase or salt form of —(CH₂)_(n)—NH₂ where n is 1 to 4. In someembodiments, each R² is, independently, C₁-C₃alkyl or the free base orsalt form of —(CH₂)_(n)—NH₂, where each n is, independently, 1 or Insome embodiments, each R² is, independently, methyl or the free base orsalt form of —(CH₂)_(n)—NH₂, where each n is, independently, 2. In someembodiments, each R² is methyl or the free base or salt form of—(CH₂)_(n)—NH₂, where each n is 2.

In some embodiments, each R³ is, independently, CF₃, C(CH₃)₃, or halo.In some embodiments, each R³ is CF₃.

In some embodiments, each R⁴ is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4. In some embodiments, each R⁴ is—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 4.

In some embodiments, G is

each X is S; each R¹ is, independently, the free base or salt form of—(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; each R² is,independently, C₁-C₈alkyl or the free base or salt form of—(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; each R³ is,independently, CF₃, C(CH₃)₃, or halo; and each R⁴ is, independently,—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 3 or 4.

In some embodiments, G is

each X is S; each R¹ is the free base or salt form of —(CH₂)_(n)—NH₂,where each n is 1 or 2; each R² is, independently, C₁-C₃alkyl or thefree base or salt form of —(CH₂)_(n)—NH₂, where each n is 2; each R³ is,independently, CF₃ or C(CH₃)₃; and each R⁴ is —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is 3 or 4.

In some embodiments, G is

each X is S; each R¹ is the free base or salt form of —(CH₂)_(n)—NH₂,where each n is 2; each R² is, independently, methyl or the free base orsalt form of —(CH₂)_(n)—NH₂, where each n is 2; each R³ is,independently, CF₃ or C(CH₃)₃; and each R⁴ is —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is 4.

In some embodiments, G is

each X is, independently, O or S; each R¹ is, independently, the freebase or salt form of —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, whereeach n is, independently, 1 to 4; each R³ is, independently, H or CF₃;and each R⁴ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4.

In some embodiments, G is

each X is, independently, O or S; each R¹ is

each R³ is, independently, H or CF₃; and each R⁴ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound chosenfrom:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the invention, the compound used for treatingand/or preventing mucositis is not Compound Y.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XI:

or a pharmaceutically acceptable salt thereof,wherein:

each X is, independently, O, S, or S(═O)₂;

each R¹ is, independently, —(CH₂)_(n)—NH₂, —(CH₂)_(p)—NH—C(═NH)NH₂, or—(CH₂)_(p)—NH—C(═O)—R⁴, where each n is, independently, 1 to 4, and eachR⁴ is, independently, H, C₁-C₃alkyl, or —(CH₂)_(p)—NH₂, where each p is,independently, 1 or 2;

each R² is, independently, H, halo, CF₃, or C(CH₃)₃; and

each V² is H, and each V¹ is, independently, —N—C(═O)—R³, where each R³is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(p)—NH—C(═NH)NH₂, where eachn is, independently, 1 to 4; or each V¹ is H and each V² is,independently, —S—R⁵, where each R⁵ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(p)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each X is S.

In some embodiments, each R¹ is, independently, —(CH₂)_(n)—NH₂,—(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴, where each n is,independently, 1 or 2, and each R⁴ is, independently, H or methyl. Insome embodiments, each R¹ is, independently, —(CH₂)_(n)—NH₂,—(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴, where each n is 2and each R⁴ is H. In some embodiments, each R¹ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 2. In someembodiments, each R¹ is —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, whereeach n is 2.

In some embodiments, each R² is, independently, H, Br, F, Cl, CF₃, orC(CH₃)₃. In some embodiments, each R² is Br, F, Cl, CF₃, or C(CH₃)₃.

In some embodiments, each V² is H and each V¹ is, independently,—N—C(═O)—R³, where each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4. In someembodiments, each V² is H and each V¹ is, independently, —N—C(═O)—R³,where each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 or 2. In someembodiments, each V² is H and each V¹ is, independently, —N—C(═O)—R³,where each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 2. In some embodiments, each V²is H and each V¹ is —N—C(═O)—R³, where each R³ is —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where n is 2.

In some embodiments, each V¹ is H and each V² is, independently, —S—R⁵,where each R⁵ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4. In someembodiments, each V¹ is H and each V² is, independently, —S—R⁵, whereeach R⁵ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is 1 or 2. In some embodiments, each V¹ is H and each V²is, independently, —S—R⁵, where each R⁵ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 2. In someembodiments, each V¹ is H and each V² is —S—R⁵, where each R⁵ is—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 2.

In some embodiments, each X is S; each R¹ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; each R² is, independently, halo, CF₃, or C(CH₃)₃;and each V¹ is H and each V² is, independently, —S—R⁵, where each R⁵ is,independently, —(CH₂)_(n)—NH₂, where each n is, independently, 1 to 4.

In some embodiments, each X is S; each R¹ is, independently,—(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; each R² is,independently, CF₃ or C(CH₃)₃; and each V¹ is H and each V² is,independently, —S—R⁵, where each R⁵ is, independently, —(CH₂)_(n)—NH₂,where each n is, independently, 1 or 2.

In some embodiments, each X is S; each R¹ is —(CH₂)_(n)—NH₂, where eachn is 1 or 2; each R² is, independently, CF₃ or C(CH₃)₃; and each V¹ is Hand each V² is —S—R⁵, where each R⁵ is —(CH₂)_(n)—NH₂, where each n is 1or 2.

In some embodiments, each X is O or S; each R¹ is, independently,—(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴,where each n is, independently, 1 to 4, and each R⁴ is, independently, Hor methyl; each R² is, independently, halo, CF₃, or C(CH₃)₃; and each V²is H, and each V¹ is, independently, —N—C(═O)—R³, where each R³ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 4.

In some embodiments, each X is S; each R¹ is, independently,—(CH₂)_(n)—NH—C(═O)—R⁴, where each n is, independently, 1 or 2, and eachR⁴ is, independently, H or methyl; each R² is, independently, halo; andeach V² is H, and each V¹ is —N—C(═O)—R³, where each R³ is—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 4.

In some embodiments, each X is O or S; each R¹ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; each R² is, independently, halo, CF₃, or C(CH₃)₃;and each V² is H, and each V¹ is, independently, —N—C(═O)—R³, where eachR³ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, whereeach n is, independently, 1 to 4.

In some embodiments, each X is O or S; each R¹ is —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 or 2; each R² is halo, CF₃,or C(CH₃)₃; and each V² is H, and each V¹ is —N—C(═O)—R³, where each R³is —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 3 or 4.

In some embodiments, each X is, independently, S or S(═O)₂; each R¹ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═O)—R⁴, where each nis, independently, 1 or 2, and each R⁴ is, independently,—(CH₂)_(p)—NH₂, where each p is, independently, 1 or 2; each R² is,independently, halo or CF₃; and each V² is H, and each V¹ is,independently, —N—C(═O)—R³, where each R³ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 3 or 4.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound chosenfrom:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the invention, the compound used for treatingand/or preventing mucositis is not Compound Z.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XII:

or a pharmaceutically acceptable salt thereof,wherein:

each Y is, independently, O, S, or NH;

each R¹ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4; and

each R² is, independently, H, halo, CF₃, or C(CH₃)₃;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each Y is, independently, O, or S. In someembodiments, each Y is O or S.

In some embodiments, each R¹ is, independently, —(CH₂)_(n)—NH₂, whereeach n is, independently, 2 to 4. In some embodiments, each R¹ is—(CH₂)_(n)—NH₂, where each n is 2 to 4.

In some embodiments, each R² is, independently, halo, CF₃, or C(CH₃)₃.In some embodiments, each R² is halo, CF₃, or C(CH₃)₃.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound whichis:

or a pharmaceutically acceptable salt thereof.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XIII:

or a pharmaceutically acceptable salt thereof,wherein:

each R¹ is, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH, CF₃, orCN;

each R² is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each R¹ is, independently, C₁-C₈alkyl, halo, OH,CF₃, or CN. In some embodiments, each R¹ is, independently, C₁-C₃alkyl,halo, CF₃, or CN. In some embodiments, each R¹ is methyl or halo. Insome embodiments, each R¹ is Br, F, or Cl.

In some embodiments, each R² is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4. In some embodiments, each R² is—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 to 4. In some embodiments,each R² is —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 or 2.

In some embodiments, each R¹ is, independently, C₁-C₈alkyl, halo, OH,CF₃, or CN; and each R² is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to

In some embodiments, each R¹ is, independently, C₁-C₃alkyl, halo, CF₃,or CN; and each R² is —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 to 4.

In some embodiments, each R¹ is methyl or halo; and each R² is—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 or 2.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound whichis:

or a pharmaceutically acceptable salt thereof.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XIV:

or a pharmaceutically acceptable salt thereof,wherein:

D is

each B is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4,

and

each X is, independently, O or S;

or a pharmaceutically acceptable salt thereof.

In some embodiments, D is

In some embodiments, each B is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4.

In some embodiments, each X is S.

In some embodiments, D is

each B is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 3 or 4, or

and each X is S.

In some embodiments, D is

each B is, independently,

and each X is, independently, O or S.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound whichis:

or a pharmaceutically acceptable salt thereof.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XV:

or a pharmaceutically acceptable salt thereof,wherein:

R¹ is H or C₁₋₁₀ alkyl;

R² is H or C₁₋₁₀ alkyl; and

m is 1 or 2.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XVI:

or a pharmaceutically acceptable salt thereof,wherein:

R¹ is H or C₁₋₈ alkyl; and

R² is H or C₁₋₈ alkyl.

In some embodiments, R¹ and R² are each, independently, H or C₁₋₈ alkyl.In some embodiments, R¹ and R² are each, independently, C₁₋₈ alkyl, C₂₋₇alkyl, C₃₋₇ alkyl, or C₃₋₆ alkyl. In some embodiments, R¹ and R² areeach, independently, 2-methylpropan-2-yl, propan-2-yl,2-methylbutan-2-yl, 2,3-dimethylbutan-2-yl, or2,3,3-trimethylbutan-2-yl. In some embodiments, R¹ and R² are each,independently, branched C₃₋₇ alkyl or branched C₃₋₆ alkyl. In someembodiments, R¹ and R² are each, independently, H or C₁₋₄ alkyl. In someembodiments, R¹ and R² are each independently, H, methyl, ethyl,propan-1-yl, propan-2-yl, butan-1-yl, butan-2-yl, or2-methylpropan-2-yl. In some embodiments, R¹ and R² are eachindependently, H, methyl, or ethyl. In some embodiments, R¹ and R² arethe same. In some embodiments, R¹ and R² are different. In someembodiments, R¹ and R² are each 2-methylpropan-2-yl.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XVII:

or a pharmaceutically acceptable salt thereof,wherein:

R¹ is H or C₁₋₈ alkyl; and

R² is H or C₁₋₈ alkyl.

In some embodiments, R¹ and R² are each, independently, H or C₁₋₈ alkyl.In some embodiments, R¹ and R² are each, independently, C₁₋₈ alkyl, C₂₋₇alkyl, C₃₋₇ alkyl, or C₃₋₆ alkyl. In some embodiments, R¹ and R² areeach, independently, propan-2-yl, 2-methylpropan-2-yl,2-methylbutan-2-yl, 2,3-dimethylbutan-2-yl, or2,3,3-trimethylbutan-2-yl. In some embodiments, R¹ and R² are each,independently, branched C₃₋₇ alkyl or branched C₃₋₆ alkyl. In someembodiments, R¹ and R² are each, independently, H or C₁₋₄ alkyl. In someembodiments, R¹ and R² are each independently, H, methyl, ethyl,propan-1-yl, propan-2-yl, butan-1-yl, butan-2-yl, or2-methylpropan-2-yl. In some embodiments, R¹ and R² are eachindependently, H, methyl, or ethyl. In some embodiments, R¹ and R² arethe same. In some embodiments, R¹ and R² are different. In someembodiments, R¹ and R² are each 2-methylpropan-2-yl.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound whichis:

or a pharmaceutically acceptable salt thereof.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XVIII:

R¹-[-X-A₁-Y—X-A₂-Y-]_(m)—R²  XVIII

or a pharmaceutically acceptable salt thereof,wherein:

each X is, independently, NR⁸, —N(R⁸)N(R⁸)—, O, or S;

each Y is, independently, C═O, C═S, O═S═O, —C(═O)C(═O)—, or—CR^(a)R^(b)—;

R^(a) and R^(b) are each, independently, hydrogen, a PL group, or an NPLgroup;

each R⁸ is, independently, hydrogen or alkyl;

A₁ and A₂ are each, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein A₁ and A₂ are,independently, optionally substituted with one or more PL group(s), oneor more NPL group(s), or a combination of one or more PL group(s) andone or more NPL group(s); or

each A₁ is, independently, optionally substituted arylene or optionallysubstituted heteroarylene, and each A₂ is a C₃ to C₈ cycloalkyl or—(CH₂)_(q)—, wherein q is 1 to 7, wherein A₁ and A₂ are, independently,optionally substituted with one or more PL group(s), one or more NPLgroup(s), or a combination of one or more PL group(s) and one or moreNPL group(s); or

each A₂ is optionally substituted arylene or optionally substitutedheteroarylene, and each A₁ is a C₃ to C₈ cycloalkyl or —(CH₂)_(q)—,wherein q is 1 to 7, wherein A₁ and A₂ are each, independently,optionally substituted with one or more PL group(s), one or more NPLgroup(s), or a combination of one or more PL group(s) and one or moreNPL group(s);

R¹ is hydrogen, a PL group, or an NPL group, and R^(e) is —X-A₁-Y—R¹¹,wherein R¹¹ is hydrogen, a PL group, or an NPL group; or

R¹ and R² are each, independently, hydrogen, a PL group, or an NPLgroup; or

R¹ and R² together are a single bond; or

R¹ is —Y-A₂-X—R′², wherein R′² is hydrogen, a PL group, or an NPL group,and R² is hydrogen, a PL group, or an NPL group;

each NPL group is, independently, —B(OR⁴)₂ or—(NR^(3′))_(q1NPL)—U^(NPL)-LK^(NPL)—(NR³)_(q2NPL)—R^(4′), wherein:

R³, R^(3′), and R^(3″) are each, independently, hydrogen, alkyl, oralkoxy;

R⁴ and R^(4′) are each, independently, hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, or heteroaryl, wherein each of the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more substitutents, wherein each substituent is,independently, alkyl, halo, or haloalkyl;

each U^(NPL) is, independently, absent or O, S, S(═O), S(═O)₂, NR³,—C(═O)—, —C(═O)—NR³—, —C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—,—C(═N—N(R³)₂)—, —C(═NR³)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—,—S—C═N—, or —C(═O)—NR³—O—, wherein groups with two chemicallynonequivalent termini can adopt both possible orientations;

each LK^(NPL) is, independently, —(CH₂)_(pNPL)— or C₂₋₈ alkenylenyl,wherein each of the —(CH₂)_(pNPL) and C₂₋₈ alkenylenyl is optionallysubstituted with one or more substituents, wherein each substituent is,independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;

each pNPL is, independently, an integer from 0 to 8;

q1NPL and q2NPL are each, independently, 0, 1, or 2;

each PL group is, independently, halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, or—(NR^(5′))_(q1PL)—U^(PL)-LK^(PL)—(NR⁵)_(q2PL)—V, wherein:

R⁵, R^(5′), and R^(5″) are each, independently, hydrogen, alkyl, oralkoxy;

each U^(PL) is, independently, absent or O, S, S(═O), S(═O)₂, NR⁵,—C(═O)—, —C(═O)—NR⁵—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—,—C(═N—N(R⁵)₂)—, —C(═NR⁵)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—,—S—C═N—, or —C(═O)—NR⁵—O—, wherein groups with two chemicallynonequivalent termini can adopt either of the two possible orientations;

each V is, independently, nitro, cyano, amino, halo, hydroxy, alkoxy,alkylthio, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to5, —C(═O)NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—C(═O)NH(CH₂)_(p)NHC(═NH)NH₂ wherein p is 1 to 5,—C(═O)NH(CH₂)_(p)NHC(═O)NH₂ wherein p is 1 to 5, —NHC(═O)-alkyl,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, ureido, carbamoyl,—C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH,S(═O)₂OH, NR^(d)R^(e), semicarbazone, aryl, cycloalkyl,heterocycloalkyl, or heteroaryl, wherein each of the aryl and cycloalkylis substituted with one or more substitutents, wherein each of theheterocycloalkyl and heteroaryl is optionally substituted with one ormore substituents, and wherein each of the substituents for the aryl,cycloalkyl, heterocycloalkyl, and heteroaryl is, independently, nitro,cyano, amino, halo, hydroxy, alkoxy, alkylthio, alkylamino,dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂,diazamino, amidino, guanidino, ureido, carbamoyl, —C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH,NR^(d)R^(e), semicarbazone, aminosulfonyl, aminoalkoxy, aminoalkythio,lower acylamino, or benzyloxycarbonyl;

each R^(c) is, independently, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, eachoptionally substituted by one or more substitutents, wherein eachsubstituent is, independently, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, orheterocycloalkyl;

R^(d) and R^(e) are, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl,wherein each of the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionallysubstituted by OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, orheterocycloalkyl;

or R^(d) and R^(e) together with the N atom to which they are attachedform a 4-, 5-, 6-, 7-, or 8-membered heterocycloalkyl;

each LK^(PL) is, independently, —(CH₂)_(pPL)— or C₂₋₈ alkenylenyl,wherein each of the —(CH₂)_(pNPL)— and C₂₋₈ alkenylenyl is optionallysubstituted with one or more substituents, wherein each substituent is,independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;

each pPL is, independently, an integer from 0-8;

q1PL and q2PL are each, independently, 0, 1, or 2; and

m is an integer from 1 to about 20.

In some embodiments, each X is, independently, NR⁸; each Y is C═O; andeach A₂ is optionally substituted arylene or optionally substitutedheteroarylene, and each A₁ is a C₃ to C₈ cycloalkyl or —(CH₂)_(q)—,wherein q is 1 to 7, wherein A₁ and A₂ are each, independently,optionally substituted with one or more PL group(s), one or more NPLgroup(s), or a combination of one or more PL group(s) and one or moreNPL group(s).

In some embodiments, each A₂ is optionally substituted phenyl, and eachA₁ is a (CH₂)—, wherein A₁ and A₂ are each, independently, optionallysubstituted with one or more PL group(s), one or more NPL group(s), or acombination of one or more PL group(s) and one or more NPL group(s).

In some embodiments, each NPL group is, independently,—(NR^(3′))_(q1NPL)—U^(NPL)-LK^(NPL)—(NR^(3″))_(q2NPL)—R^(4′), wherein:R³, R^(3′), and R^(3″) are each, independently, hydrogen, alkyl, oralkoxy; and R⁴ and R^(4′) are each, independently, hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl, wherein each of thealkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more substitutents, wherein each substituent is,independently, alkyl, halo, or haloalkyl.

In some embodiments, each NPL group is, independently, —B(OR⁴)₂, R^(4′),or OR^(4′), and R⁴ and R^(4′) are each, independently, alkyl, alkenyl,alkynyl, cycloalkyl, or aryl, each is optionally substituted with one ormore substitutents, wherein each substituent is, independently, alkyl,halo, or haloalkyl.

In some embodiments, each NPL group is, independently, R^(4′) orOR^(4′), and each R^(4′) is, independently, alkyl, alkenyl, alkynyl,cycloalkyl, or aryl, each is optionally substituted with one or moresubstitutents, wherein each substituent is, independently, alkyl, halo,or haloalkyl.

In some embodiments, each NPL group is, independently, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, or alkoxy, each is optionally substitutedwith one or more substitutents, wherein each substituent is,independently, alkyl, halo, or haloalkyl. In some embodiments, each NPLgroup is, independently, alkyl, haloalkyl, alkoxy, or haloalkoxy.

In some embodiments, each V is, independently, nitro, cyano, amino,hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino,ureido, carbamoyl, —C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂,—NH—S(═O)₂OH, S(═O)₂OH, NR^(d)R^(e), semicarbazone, aryl,heterocycloalkyl, or heteroaryl, wherein the aryl is substituted withone or more substitutents, wherein each of the heterocycloalkyl andheteroaryl is optionally substituted with one or more substituents, andwherein each of the substituents for the aryl, heterocycloalkyl, andheteroaryl is, independently, nitro, cyano, amino, hydroxy, alkoxy,alkylthio, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to5, —N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, ureido, carbamoyl,—C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH,S(═O)₂OH, NR^(d)R^(e), semicarbazone, aminosulfonyl, aminoalkoxy,aminoalkythio, lower acylamino, or benzyloxycarbonyl.

In some embodiments, each V is, independently, hydroxy, amino,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, carbamoyl, —C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH,NR^(d)R^(e), a substituted aryl group, heterocycloalkyl, or heteroaryl,wherein each of the heterocycloalkyl and heteroaryl is optionallysubstituted with one more substituents, wherein each substituent is,independently, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, cyano,nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂,amidino, guanidino, aminosulfonyl, aminoalkoxy, aminoalkythio, loweracylamino, or benzyloxycarbonyl; and wherein the substituted aryl groupis substituted with one more substituents, wherein each substituent is,independently, amino, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein pis 1 to 5, —N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl,aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl.

In some embodiments, each V is, independently, hydroxy, amino,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, carbamoyl, —C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH,NR^(d)R^(e), a substituted aryl group, heterocycloalkyl, or heteroaryl,wherein each of the heterocycloalkyl and heteroaryl is optionallysubstituted with one more substituents, wherein each substituent is,independently, amino, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein pis 1 to 5, —N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl,aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl; andwherein the substituted aryl group is substituted with one moresubstituents, wherein each substituent is, independently, amino, cyano,nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂,amidino, guanidino, aminosulfonyl, aminoalkoxy, aminoalkythio, loweracylamino, or benzyloxycarbonyl.

In some embodiments, each V is, independently, hydroxy, amino,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, carbamoyl, —C(═O)NH—OH,—O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, NR^(d)R^(e), heterocycloalkyl, orheteroaryl, wherein each of the heterocycloalkyl and heteroaryl isoptionally substituted with one more substituents, wherein eachsubstituent is, independently, alkyl, haloalkyl, alkoxy, haloalkoxy,amino, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl, aminoalkoxy,aminoalkythio, lower acylamino, or benzyloxycarbonyl.

In some embodiments, each V is, independently, hydroxy, amino,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, carbamoyl, —C(═O)NH—OH,—O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, NR^(d)R^(e), heterocycloalkyl, orheteroaryl, wherein each of the heterocycloalkyl and heteroaryl isoptionally substituted with one more substituents, wherein eachsubstituent is, independently, amino, cyano, nitro, hydroxy,—NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, amidino, guanidino,aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, orbenzyloxycarbonyl.

In some embodiments, each V is, independently, hydroxy, amino,alkylamino, arylamino, heteroarylamino, ureido, guanidino, carbamoyl,—C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH,S(═O)₂OH, a 3-8 membered heterocycloalkyl, a 5- to 10-memberedheteroaryl, or a 6- to 10-membered substituted aryl, wherein thesubstituted aryl is substituted with one or more substituents, whereineach substituent is, independently, OH, amino, hydroxylalkyl, oraminoalkyl, and wherein each of the 3-8 membered heterocycloalkyl andthe 5- to 10-membered heteroaryl is optionally substituted with one ormore substituents, wherein each substituent is, independently, alkyl,haloalkyl, alkoxy, haloalkoxy, amino, cyano, nitro, hydroxy,—NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, amidino, guanidino,aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, orbenzyloxycarbonyl.

In some embodiments, each V is, independently, hydroxy, amino,alkylamino, arylamino, heteroarylamino, ureido, guanidino, carbamoyl,—C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH,S(═O)₂OH, a 3-8 membered heterocycloalkyl, a 5- to 10-memberedheteroaryl, or a 6- to 10-membered substituted aryl, wherein thesubstituted aryl is substituted with one or more substituents, whereineach substituent is, independently, OH, amino, hydroxylalkyl, oraminoalkyl.

In some embodiments, each V is, independently, amino, heteroarylamino,ureido, guanidino, carbamoyl, C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH,—O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH, aziridinyl, azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholino, azepanyl, azocanyl,tetrazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, imidazolyl, pyridinyl,indolyl, or a substituted phenyl, wherein the substituted phenyl issubstituted with one or more substituents, wherein each substituent is,independently, OH or amino.

In some embodiments, each V is, independently, amino, alkylamino,dialkylamino, NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂,guanidino, amidino, ureido, heterocycloalkyl, or heteroaryl, whereineach of the heterocycloalkyl and heteroaryl is optionally substitutedwith one more substituents, wherein each substituent is, independently,amino, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl, aminoalkoxy,aminoalkythio, lower acylamino, or benzyloxycarbonyl.

In some embodiments, each V is, independently, amino, alkylamino,dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂,guanidino, amidino, ureido, pyrrodinyl, piperidinyl, piperazinyl,4-methylpiperazinyl, pyridinyl, pyrimidinyl, pyrazinyl, or indolyl. Insome embodiments, each V is, independently, amino, alkylamino,dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂,guanidino, amidino, ureido, or indolyl.

In some embodiments, each PL group is, independently, halo,ydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, or—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5″))_(q2PL)—V.

In some embodiments, each PL group is, independently, halo,—(CH₂)_(pPL)—V, O—(CH₂)_(pPL)—V, and S—(CH₂)_(pPL)—V; each pPL is aninteger from 0 to 5; and each V is, independently, hydroxy, amino, halo,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, carbamoyl, —C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH,NR^(d)R^(e), a substituted aryl group, heterocycloalkyl, or heteroaryl,wherein each of the heterocycloalkyl and heteroaryl is optionallysubstituted with one more substituents, wherein each substituent is,independently, amino, halo, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl,aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl; andwherein the substituted aryl group is substituted with one moresubstituents, wherein each substituent is, independently, amino, halo,cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl, aminoalkoxy,aminoalkythio, lower acylamino, or benzyloxycarbonyl.

In some embodiments, each PL group is, independently, halo,—(CH₂)_(pPL)—V, O—(CH₂)_(pPL)—V, and S—(CH₂)_(pPL)—V; each pPL is aninteger from 0 to 5; and each V is, independently, hydroxy, amino,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, carbamoyl, —C(═O)NH—OH,—O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, NR^(d)R^(e), heterocycloalkyl, orheteroaryl, wherein each of the heterocycloalkyl and heteroaryl isoptionally substituted with one more substituents, wherein eachsubstituent is, independently, amino, halo, cyano, nitro, hydroxy,—NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, amidino, guanidino,aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, orbenzyloxycarbonyl.

In some embodiments, each NPL group is, independently, —B(OR⁴)₂, R^(4′),or OR^(4′), R⁴ and R^(4′) are each, independently, alkyl, alkenyl,alkynyl, cycloalkyl, or aryl, each is optionally substituted with one ormore substitutents, wherein each substituent is, independently, alkyl,halo, or haloalkyl; each PL group is, independently, halo,—(CH₂)_(pPL)—V, O—(CH₂)_(pPL)—V, or S—(CH₂)_(pPL)—V; each pPL is aninteger from 0 to 5; and each V is, independently, hydroxy, amino, halo,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, carbamoyl, —C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH,NR^(d)R^(e), a substituted aryl group, heterocycloalkyl, or heteroaryl,wherein each of the heterocycloalkyl and heteroaryl is optionallysubstituted with one more substituents, wherein each substituent is,independently, amino, halo, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl,aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl; andwherein the substituted aryl group is substituted with one moresubstituents, wherein each substituent is, independently, amino, halo,cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl, aminoalkoxy,aminoalkythio, lower acylamino, or benzyloxycarbonyl.

In some embodiments, each NPL group is, independently, R^(4′) orOR^(4′), R⁴ and R^(4′) are each, independently, alkyl, alkenyl, alkynyl,cycloalkyl, or aryl, each is optionally substituted with one or moresubstitutents, wherein each substituent is, independently, alkyl, halo,or haloalkyl; each PL group is, independently, halo, —(CH₂)_(pPL)—V,O—(CH₂)_(pPL)—V, or S—(CH₂)_(pPL)—V; each pPL is an integer from 0 to 5;and each V is, independently, hydroxy, amino, alkylamino, dialkylamino,—NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, guanidino, amidino,ureido, carbamoyl, —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH,NR^(d)R^(e), heterocycloalkyl, or heteroaryl, wherein each of theheterocycloalkyl and heteroaryl is optionally substituted with one moresubstituents, wherein each substituent is, independently, amino, halo,cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl, aminoalkoxy,aminoalkythio, lower acylamino, or benzyloxycarbonyl.

In some embodiments, each A₂ is phenyl optionally substituted with oneor more substituents, wherein each substituent is, independently,OR^(4′), halo, O—(CH₂)_(pPL)—V, or S—(CH₂)_(pPL)—V; and each A₁ is a—(CH₂)— group optionally substituted with one or more substituents,wherein each substituent is, independently, alkyl or —(CH₂)_(pPL)—V.

In some embodiments, each A₂ is phenyl optionally substituted with oneor more substituents, wherein each substituent is, independently,O-alkyl, halo, or O—(CH₂)_(pPL)—V, wherein pPL is an integer from 1 to5; each A₁ is a —(CH₂)— group optionally substituted with one or moresubstituents, wherein each substituent is, independently, CH₃ or—(CH₂)_(pPL)—V, wherein pPL is an integer from 1 to 5; and each V is,independently, hydroxy, amino, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido,carbamoyl, —C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂,—NH—S(═O)₂OH, S(═O)₂OH, NR^(d)R^(e), a substituted aryl group, asubstituted cycloalkyl group, heterocycloalkyl, or heteroaryl, whereineach of the heterocycloalkyl and heteroaryl is optionally substitutedwith one more substituents, wherein each substituent is, independently,amino, halo, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl, aminoalkoxy,aminoalkythio, lower acylamino, or benzyloxycarbonyl; and wherein eachof the substituted aryl group and the substituted cycloalkyl group issubstituted with one more substituents, wherein each substituent is,independently, amino, halo, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl,aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl.

In some embodiments, each A₂ is phenyl optionally substituted with oneor more substituents, wherein each substituent is, independently,O-alkyl, halo, or O—(CH₂)_(pPL)—V, wherein pPL is an integer from 1 to5; each A₁ is a —(CH₂)— group optionally substituted with one or moresubstituents, wherein each substituent is, independently, CH₃ or—(CH₂)_(pPL)—V, wherein pPL is an integer from 1 to 5; and each V is,independently, hydroxy, amino, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido,carbamoyl, —C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂,—NH—S(═O)₂OH, S(═O)₂OH, NR^(d)R^(e), a substituted aryl group, asubstituted cycloalkyl group, heterocycloalkyl, or heteroaryl, whereineach of the heterocycloalkyl and heteroaryl is optionally substitutedwith one more substituents, wherein each substituent is, independently,amino, halo, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl, aminoalkoxy,aminoalkythio, lower acylamino, or benzyloxycarbonyl; and wherein eachof the substituted aryl group and the substituted cycloalkyl group issubstituted with one more substituents, wherein each substituent is,independently, amino, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein pis 1 to 5, —N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl,aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl.

In some embodiments, each A₂ is phenyl optionally substituted with oneor more substituents, wherein each substituent is, independently,O-alkyl, halo, or O—(CH₂)_(pPL)—V, wherein pPL is an integer from 1 to5; each A₁ is a —(CH₂)— group optionally substituted with one or moresubstituents, wherein each substituent is, independently, CH₃ or—(CH₂)_(pPL)—V, wherein pPL is an integer from 1 to 5; and each V is,independently, hydroxy, amino, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido,carbamoyl, —C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂,—NH—S(═O)₂OH, S(═O)₂OH, NR^(d)R^(e), a substituted aryl group,heterocycloalkyl, or heteroaryl, wherein each of the heterocycloalkyland heteroaryl is optionally substituted with one more substituents,wherein each substituent is, independently, amino, halo, cyano, nitro,hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, amidino,guanidino, aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino,or benzyloxycarbonyl; and wherein the substituted aryl group issubstituted with one more substituents, wherein each substituent is,independently, amino, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein pis 1 to 5, —N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl,aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl.

In some embodiments, each A₂ is phenyl optionally substituted with oneor more substituents, wherein each substituent is, independently,O—(CH₃); halo, or O—(CH₂)₂—V; each A₁ is a —(CH₂)— group optionallysubstituted with one substituent, wherein each substituent is,independently, CH₃, (CH₂)—V, (CH₂)₂—V, (CH₂)₃—V, —(CH₂)₄—V, or—(CH₂)₅—V; and each V is, independently, hydroxy, amino, alkylamino,arylamino, heteroarylamino, ureido, guanidino, carbamoyl, —C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH, a3-8 membered heterocycloalkyl, a 5- to 10-membered heteroaryl, or a 6-to 10-membered substituted aryl, wherein the substituted aryl issubstituted with one or more substituents, wherein each substituent is,independently, OH, amino, hydroxylalkyl, or aminoalkyl.

In some embodiments, each A₂ is phenyl optionally substituted with oneor more substituents, wherein each substituent is, independently,O—(CH₃), halo, or O—(CH₂)₂—V; each

A₁ is a —(CH₂)— group optionally substituted with one substituent,wherein each substituent is, independently, CH₃, (CH₂)—V, (CH₂)₃—V,—(CH₂)₄—V, and —(CH₂)₅—V; and each V is, independently, hydroxyl, amino,heteroarylamino, ureido, guanidino, carbamoyl, C(═O)OH, —C(═O)OR^(c),—C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH, aziridinyl,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino,azepanyl, azocanyl, tetrazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,imidazolyl, pyridinyl, indolyl, or a substituted phenyl,

wherein the substituted phenyl is substituted with one or moresubstituents, wherein each substituent is, independently, OH or amino.

In some embodiments, each A₂ is phenyl optionally substituted with oneor more substituents, wherein each substituent is, independently,O—(CH₃), halo, or O—(CH₂)₂—V; each

A₁ is a —(CH₂)— group optionally substituted with one substituent,wherein each substituent is, independently, (CH₂)—V, (CH₂)₃—V,—(CH₂)₄—V, and —(CH₂)₅—V; and each V, is independently, hydroxyl, amino,ureido, guanidino, carbamoyl, or indolyl.

In some embodiments, each A₂ is phenyl optionally substituted with oneor more substituents, wherein each substituent is, independently,O—(CH₃), halo, or O—(CH₂)₂—V; each

A₁ is a —(CH₂)— group optionally substituted with one substituent,wherein each substituent is, independently, (CH₂)—V, (CH₂)₃—V,—(CH₂)₄—V, and —(CH₂)₅—V; and each V, is independently, amino, ureido,guanidino, carbamoyl, or indolyl.

In some embodiments, each A₂ is phenyl optionally substituted with oneor more substituents, wherein each substituent is, independently,O—(CH₃), halo, or O—(CH₂)₂—V; each

A₁ is a —(CH₂)— group optionally substituted with one substituent,wherein each substituent is, independently, CH₃, —(CH₂)—V, —(CH₂)₂—V,—(CH₂)₃—V, —(CH₂)₄—V, or —(CH₂)₅—V; each V is, independently, hydroxyl,amino, heteroarylamino, ureido, guanidino, carbamoyl, C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH,aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholino, azepanyl, azocanyl, tetrazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, imidazolyl, pyridinyl, indolyl, or a substitutedphenyl,

wherein the substituted phenyl is substituted with one or moresubstituents, wherein each substituent is, independently, OH or amino;and at least one of A₁ is a —(CH₂)— group substituted with onesubstituent, wherein each substituent is, independently, (CH₂)—V¹,(CH₂)₂—V¹, —(CH₂)₃—V¹, —(CH₂)₄—V¹, or —(CH₂)₅—V¹, wherein V¹ is indolyl.

In some embodiments, R¹ is hydrogen, —C(═NR³)—NR³″R^(4′),—C(═O)—(CH₂)_(pNPL)—R^(4′), —C(═O)—(CH₂)_(pPL)—V,—C(═O)-A₂-NH—C(═O)—(CH₂)_(pPL)—V; or—C(═O)-A₂-NH—C(═O)—(CH₂)_(pNPL)—R^(4′); and R² is NH₂,—NH—(CH₂)_(pPL)—V, or NH-A₁-C(═O)—NH₂.

In some embodiments, R¹ is hydrogen, —C(═NR³)—NR³″R^(4′),—C(═O)—(CH₂)_(pNPL)—R^(4′), —C(═O)—(CH₂)_(pPL)—V,—C(═O)-A₂-NH—C(═O)—(CH₂)_(pPL)—V, or—C(═O)-A₂-NH—C(═O)—(CH₂)_(pNPL)—R^(4′), wherein each V is,independently, hydroxy, amino, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido,carbamoyl, heterocycloalkyl, or heteroaryl, and where R³, R^(3″), andR^(4′) are each, independently, H or alkyl; and R² is NH₂,—NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —NH—(CH₂)_(pPL)—V, orNH-A₁-C(═O)—NH₂, wherein V is hydroxy, amino, alkylamino, dialkylamino,—NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, guanidino, amidino,ureido, carbamoyl, heterocycloalkyl, or heteroaryl.

In some embodiments, R¹ is hydrogen, —C(═NH)—NH₂, —C(═O)—R^(4′),—C(═O)—(CH₂)_(pPL)—V, —C(═O)-A₂-NH—C(═O)—(CH₂)_(pPL)—V, or—C(═O)-A₂-NH—C(═O)—R⁴, wherein each V is, independently, amino,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein

p is 1 to 5, —N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, carbamoyl,heterocycloalkyl, or heteroaryl, and where R^(4′) is alkyl; and R² isNH₂, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —NH—(CH₂)_(pPL)—V, orNH-A₁-C(═O)—NH₂, wherein V is amino, alkylamino, dialkylamino,—NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, guanidino, amidino,ureido, or carbamoyl.

In some embodiments, m is 3 or 4. In some embodiments, m is 4. In someembodiments, at least one of A₂ group is different from other A₂ groups.In some embodiments, all A₂ groups are the same.

In some embodiments, at least one of A₁ group is different from other A₁groups. In some embodiments, all A₁ groups are the same. In someembodiments, the compound is a compound of Formula XVIIIa:

or pharmaceutically acceptable salt thereof, wherein:

each R⁹ is, independently, H, a PL group, or an NPL group;

each R¹⁰ is, independently, H, a PL group, or an NPL group;

each R^(11a) is, independently, a PL group or an NPL group; and

each t1 is, independently, 0, 1, or 2.

In some embodiments, each R⁹ is, independently, a PL group or an NPLgroup. In some embodiments, each R⁹ is, independently, alkyl or(CH₂)_(pPL)—V wherein pPL is an integer from 1 to 5. In someembodiments, each R⁹ is, independently, (CH₂)_(pPL)—V wherein pPL is aninteger from 1 to 5.

In some embodiments, each R¹⁰ is H.

In some embodiments, each R^(11a) is, independently, halo, alkyl,alkoxy, haloalkyl, haloalkoxy, —(CH₂)_(pPL)—V, —O(CH₂)_(pPL)—V, or—S(CH₂)_(pPL)—V, wherein pPL is an integer from 1 to 5. In someembodiments, each R^(11a) is, independently, halo, alkyl, alkoxy,haloalkyl, or haloalkoxy. In some embodiments, each R^(11a) is,independently, alkoxy. In some embodiments, each R^(11a) is methoxy.

In some embodiments, the compound is a compound of Formula XVIIIa-1,XVIIIa-2, or XVIIIa-3:

or pharmaceutically acceptable salt thereof, wherein each R¹¹ is,independently, H, alkyl, haloalkyl, or —(CH₂)_(pPL)—V, wherein pPL is aninteger from 1 to 5.

In some embodiments, in Formula XVIIIa-2 or XVIIIa-3, orpharmaceutically acceptable salt thereof, each R¹¹ is, independently,alkyl.

In some embodiments, each R¹¹ is methyl.

The compounds of Formula XVIII, XVIIIa, XVIIIa-1, XVIIIa-2, or XVIIIa-3(such as the polymers and oligomers), or salts thereof, useful in thepresent invention can be made, for example, by methods described in U.S.Patent Application Publication No. 2006-0041023, U.S. Pat. No.7,173,102, and International Application No. WO 2005/123660. In someembodiments, the compounds of Formula XVIII, XVIIIa, XVIIIa-1, XVIIIa-2,or XVIIIa-3 (such as the polymers and oligomers), or salts thereof,useful in the present invention can be selected from those described inU.S. Patent Application Publication No. 2006-0041023, U.S. Pat. No.7,173,102, and International Application No. WO 2005/123660. In someembodiments, the compound of Formula XVIII, XVIIIa, XVIIIa-1, XVIIIa-2,or XVIIIa-3 (such as the polymers and oligomers), or salts thereof,useful in the present invention is a compound or salt thereof selectedfrom those described in U.S. Patent Application Publication No.2006-0041023, U.S. Pat. No. 7,173,102, and International Application No.WO 2005/123660.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XIX:

R¹-[-X-A₁-X—Y-A₂-Y-]_(m)-R²  XIX

or a pharmaceutically acceptable salt thereof,wherein:

each X is, independently, NR⁸, O, S, —N(R⁸)N(R⁸)—, —N(R⁸)—(N═N)—,—(N═N)—N(R⁸)—, —C(R⁷R^(7′))NR⁸—, —C(R⁷R^(7′))O—, or —C(R⁷R^(7′))S—;

each Y is, independently, C═O, C═S, O═S═O, —C(═O)C(═O)—, C(R⁶R^(6′))C═O,or C(R⁶R^(6′))C═S;

each R⁸ is, independently, hydrogen or alkyl;

each R⁷ and each R⁷ are, independently, hydrogen or alkyl; or R⁷ andR^(7′) together form —(CH₂)_(p)—, wherein p is 4 to 8;

each R⁶ and each R^(6′) are, independently, hydrogen or alkyl; or R⁶ andR^(6′) together form —(CH₂)₂NR¹²(CH₂)₂—, wherein R¹² is hydrogen,—C(═N)CH₃, or —C(═NH)—NH₂;

A₁ and A₂ are each, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein A₁ and A₂ are each,independently, optionally substituted with one or more PL group(s), oneor more NPL group(s), or a combination of one or more PL group(s) andone or more NPL group(s);

or each A₂ is, independently, optionally substituted arylene oroptionally substituted heteroarylene, and each A₁ is, independently,optionally substituted C₃ to C₈ cycloalkyl, wherein A₁ and A₂ are each,independently, optionally substituted with one or more PL group(s), oneor more NPL group(s), or a combination of one or more PL group(s) andone or more NPL group(s);

R¹ is hydrogen, a PL group, or an NPL group, and R² is —X-A₁-X—R¹,wherein A₁ is as defined above and is optionally substituted with one ormore PL group(s), one or more NPL group(s), or a combination of one ormore PL group(s) and one or more NPL group(s); or

R¹ is hydrogen, a PL group, or an NPL group, and R² is —X-A¹-X—R¹,wherein A′ is C₃ to C₈ cycloalkyl, aryl, or heteroaryl and is optionallysubstituted with one or more PL group(s), one or more NPL group(s), or acombination of one or more PL group(s) and one or more NPL group(s); or

R¹ is —Y-A₂-Y—R², and each R² is, independently, hydrogen, a PL group,or an NPL group; or

R¹ is —Y-A¹ and R² is —X-A′, wherein each A′ is, independently, C₃ to C₈cycloalkyl, aryl, or heteroaryl and is optionally substituted with oneor more PL group(s), one or more NPL group(s), or a combination of oneor more PL group(s) and one or more NPL group(s); or

R¹ and R² are, independently, a PL group or an NPL group; or

R¹ and R² together form a single bond;

each NPL is, independently, —B(OR⁴)₂ or—(NR^(3′))_(q1NPL)—U^(NPL)-LK^(NPL)—(NR^(3″))_(q2NPL)—R^(4′),

wherein:

R³, R^(3′), and R^(3″) are each, independently, hydrogen, alkyl, oralkoxy;

R⁴ and R^(4′) are each, independently, hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, and heteroaryl, wherein each of the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more alkyl or halo groups;

each U^(NPL) is, independently, absent or O, S, S(═O), S(═O)₂, NR³,—C(═O)—, —C(═O)—NR³—, —C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—,—C(═N—N(R³)₂)—, —C(═NR³)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—,—S—C═N—, or —C(═O)—NR³—O—, wherein groups with two chemicallynonequivalent termini can adopt both possible orientations;

each LK^(NPL) is, independently, —(CH₂)_(pNPL)— or C₂₋₈ alkenylenyl,wherein each of the —(CH₂)_(pNPL)— and C₂₋₈ alkenylenyl is optionallysubstituted with one or more substituents, wherein each substituent is,independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;

each pNPL is, independently, an integer from 0 to 8;

q1NPL and q2NPL are each, independently, 0, 1, or 2;

each PL is, independently, halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, or—(NR^(5′))_(q1PL)—U^(PL)-LK^(PL)—(NR^(5′))_(q2PL)—V, wherein:

R⁵, R^(5′), and R^(5″) are each, independently, hydrogen, alkyl, andalkoxy;

each U^(PL) is, independently, absent or O, S, S(═O), S(═O)₂, NR⁵,—C(═O)—, —C(═O)—NR⁵—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—,—C(═N—N(R⁵)₂)—, —C(═NR⁵)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—,—S—C═N—, or —C(═O)—NR⁵—O—, wherein groups with two chemicallynonequivalent termini can adopt either of the two possible orientations;

each V is, independently, nitro, cyano, amino, halo, hydroxy, alkoxy,alkylthio, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to5, —C(═O)NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—C(═O)NH(CH₂)_(p)NHC(═NH)NH₂ wherein p is 1 to 5,—C(═O)NH(CH₂)_(p)NHC(═O)NH₂ wherein p is 1 to 5, —NHC(═O)-alkyl,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, ureido, carbamoyl,—C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH,S(═O)₂OH, NR^(d)R^(e), semicarbazone, aryl, cycloalkyl,heterocycloalkyl, or heteroaryl, wherein each of the aryl and cycloalkylis substituted with one or more substitutents, wherein each of theheterocycloalkyl, and heteroaryl is optionally substituted with one ormore substituents, and wherein each of the substituents for the aryl,cycloalkyl, heterocycloalkyl, and heteroaryl is, independently, nitro,cyano, amino, halo, hydroxy, alkoxy, alkylthio, alkylamino,dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂,diazamino, amidino, guanidino, ureido, carbamoyl, —C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH,NR^(d)R^(e), semicarbazone, aminosulfonyl, aminoalkoxy, aminoalkythio,lower acylamino, or benzyloxycarbonyl;

each LK^(PL) is, independently, —(CH₂)_(pPL)— or C₂₋₈ alkenylenyl,wherein each of the —(CH₂)_(pNPL)— and C₂₋₈ alkenylenyl is optionallysubstituted with one or more substituents, wherein each substituent is,independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;

each pPL is, independently, an integer from 0 to 8;

q1PL and q2PL are each, independently, 0, 1, or 2; and

m is an integer from 1 to about 20.

In some embodiments, each of the moiety of —Y-A₂-Y— is, independently, amoiety of Formula XIX-1, XIX-2, or XIX-3:

wherein each R^(12a) is, independently, a PL group or an NPL group; andt2 is 0, 1, or 2.

In some embodiments, each of the moiety of —Y-A₂-Y— is, independently, amoiety of Formula XIX-1 or XIX-2; and each R^(12a) is, independently,halo, alkyl, alkoxy, haloalkyl, haloalkoxy, —(CH₂)_(pPL)—V,—O(CH₂)_(pPL)—V, or —S(CH₂)_(pPL)—V, wherein pPL is an integer from 1 to5.

In some embodiments, each R^(12a) is, independently, halo, alkyl,alkoxy, haloalkyl, or haloalkoxy. In some embodiments, each R^(12a) is,independently, alkoxy. In some embodiments, each R^(12a) is methoxy.

In some embodiments, each of the moiety of —Y-A₂-Y— is, independently, amoiety of Formula XIX-1 or XIX-2; and t2 is 2.

In some embodiments, each R^(12a) is, independently, alkoxy. In someembodiments, each R^(12a) is methoxy.

In some embodiments, each of the moiety of —Y-A₂-Y— is, independently, amoiety of Formula XIX-1, and the moiety of Formula XIX-1 is a moiety ofFormula XIX-1a:

In some embodiments, each of the moiety of —X-A₁-X— is, independently, amoiety of Formula XIX-B:

wherein each R^(13a) is, independently, a PL group or an NPL group; andt3 is 0, 1, or 2.

In some embodiments, each of the moiety of —X-A₁-X— is, independently, amoiety of Formula XIX-C:

wherein each of R^(13a-1) and R^(13a-2) is, independently, H, a PLgroup, or an NPL group.

In some embodiments, each of R^(13a-1) and R^(13a-2) is, independently,a PL group or an NPL group. In some embodiments, each of R^(13a-1) andR^(13a-2) is, independently, halo, alkyl, haloalkyl, —O(CH₂)_(pPL)—V, or—S(CH₂)_(pPL)—V, wherein pPL is an integer from 1 to 5. In someembodiments, each of R^(13a-1) and R^(13a-2) is, independently,haloalkyl or —S(CH₂)_(pPL)—V, wherein pPL is an integer from 1 to 5.

In some embodiments, each of the moiety of —X-A₁-X— is, independently, amoiety of Formula XIX-D:

wherein each R^(14a) is, independently, a PL group or an NPL group; andt4 is 0, 1, or 2.

In some embodiments, t4 is 0.

In some embodiments, each moiety of —Y-A₂-Y— is, independently, a moietyof Formula XIX-1, XIX-1a, XIX-2, or XIX-3; and each of the moiety of—X-A₁-X— is, independently, a moiety of Formula XIX-B, XIX-C, or XIX-D.In some embodiments, each moiety of —Y-A₂-Y— is, independently, a moietyof Formula XIX-1 or XIX-1a; and each of the moiety of —X-A₁-X— is,independently, a moiety of Formula XIX-B or XIX-C. In some embodiments,each moiety of —Y-A₂-Y— is, independently, a moiety of Formula XIX-1a;and each of the moiety of —X-A₁-X— is, independently, a moiety ofFormula XIX-C. In some embodiments, each moiety of —Y-A₂-Y— is,independently, a moiety of Formula XIX-1, XIX-1a, XIX-2, or XIX-3; andeach of the moiety of —X-A₁-X— is, independently, a moiety of FormulaXIX-D. In some embodiments, each moiety of —Y-A₂-Y— is, independently, amoiety of Formula XIX-1a.

In some embodiments, the compound is of Formula XIXa:

R¹—X-A₁-X—Y-A₂-Y—X-A₁-X—R²  XIXa

or pharmaceutically acceptable salt thereof, wherein:

each X is, independently, NR⁸, O, S, or —N(R⁸)N(R⁸)—;

each Y is, independently, C═O, C═S, or O═S═O;

each R⁸ is, independently, hydrogen or alkyl;

A₁ and A₂ are each, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein A₁ and A₂ are each,independently, optionally substituted with one or more PL group(s), oneor more NPL group(s), or a combination of one or more PL group(s) andone or more NPL group(s);

R¹ is a PL group or an NPL group;

R² is R¹;

each NPL is, independently,—(NR^(3′))_(q1NPL)—U^(NPL)-LK^(NPL)—(NR^(3″))_(q2NPL)—R^(4′), wherein:

R³, R^(3′), and R^(3″) are each, independently, hydrogen, alkyl, oralkoxy;

R⁴ and R^(4′) are each, independently, hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, or heteroaryl, wherein each of the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more alkyl or halo groups;

U^(NPL) is, independently, absent or O, S, S(═O), S(═O)₂, NR³, —C(═O)—,—C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —S—C═N—, or —C(═O)—NR³—O—,wherein groups with two chemically nonequivalent termini can adopteither of the two possible orientations;

each LK^(NPL) is, independently, —(CH₂)_(pNPL)— or C₂₋₈ alkenylenyl,wherein the —(CH₂)_(pNPL)— is optionally substituted with one or moresubstituents, wherein each substituent is, independently, amino,hydroxyl, or alkyl;

each pNPL is, independently, an integer from 0 to 8;

q1NPL and q2NPL are each, independently, 0, 1, or 2;

each PL is, independently, halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, or—(NR^(5′))_(q1PL)—U^(PL)-LK^(PL)—(NR^(5′))_(q2PL)—V, wherein:

R⁵, R^(5′), and R^(5″) are each, independently, hydrogen, alkyl, oralkoxy;

each U^(PL) is, independently, absent or O, S, S(═O), S(═O)₂, NR⁵,—C(═O)—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—,—C(═NR⁵)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵O—, —R⁵S—,—S—C═N—, or —C(═O)—NR⁵—O—, wherein groups with two chemicallynonequivalent termini can adopt both possible orientations;

each V is, independently, nitro, cyano, amino, halo, hydroxy, alkoxy,alkylthio, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to5, —N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, ureido, carbamoyl,—C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH,S(═O)₂OH, NR^(d)R^(e), semicarbazone, aryl, heterocycloalkyl, orheteroaryl, wherein the aryl is substituted with one or moresubstitutents, wherein each of the heterocycloalkyl and heteroaryl isoptionally substituted with one or more substituents, and wherein eachof each of the substituents for the aryl, heterocycloalkyl, andheteroaryl is, independently, nitro, cyano, amino, halo, hydroxy,alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein pis 1 to 5, —N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, ureido,carbamoyl, —C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂,—NH—S(═O)₂OH, S(═O)₂OH, NR^(d)R^(e), semicarbazone, aminosulfonyl,aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl;

each LK^(PL) is, independently, —(CH₂)_(pPL)— or C₂₋₈ alkenylenyl,wherein the —(CH₂)_(pNPL)— is optionally substituted with one or moresubstituents, wherein each substituent is, independently, amino,hydroxyl, or alkyl;

each pPL is, independently, an integer from 0 to 8; and

q1PL and q2PL are each, independently, 0, 1, or 2.

In some embodiments, each NPL group is, independently, —B(OR⁴)₂, R^(4′),or OR^(4′), and R⁴ and R^(4′) are each, independently, alkyl, alkenyl,alkynyl, cycloalkyl, or aryl, each is optionally substituted with one ormore substitutents, wherein each substituent is, independently, alkyl,halo, or haloalkyl.

In some embodiments, each NPL group is, independently, R^(4′) orOR^(4′), and each R^(4′) is, independently, alkyl, alkenyl, alkynyl,cycloalkyl, or aryl, each is optionally substituted with one or moresubstitutents, wherein each substituent is, independently, alkyl, halo,or haloalkyl.

In some embodiments, each NPL group is, independently, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, or alkoxy, each is optionally substitutedwith one or more substitutents, wherein each substituent is,independently, alkyl, halo, or haloalkyl. In some embodiments, each NPLgroup is, independently, alkyl, haloalkyl, alkoxy, or haloalkoxy.

In some embodiments, each V is, independently, nitro, cyano, amino,hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino,ureido, carbamoyl, —C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂,—NH—S(═O)₂OH, S(═O)₂OH, NR^(d)R^(e), semicarbazone, aryl,heterocycloalkyl, or heteroaryl, wherein the aryl is substituted withone or more substitutents, wherein each of the heterocycloalkyl andheteroaryl is optionally substituted with one or more substituents, andwherein each of each of the substituents for the aryl, heterocycloalkyl,and heteroaryl is, independently, nitro, cyano, amino, hydroxy, alkoxy,alkylthio, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to5, —N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, ureido, carbamoyl,—C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH,S(═O)₂OH, NR^(d)R^(e), semicarbazone, aminosulfonyl, aminoalkoxy,aminoalkythio, lower acylamino, or benzyloxycarbonyl.

In some embodiments, each V is, independently, hydroxy, amino,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, carbamoyl, —C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH,NR^(d)R^(e), a substituted aryl group, heterocycloalkyl, or heteroaryl,wherein each of the heterocycloalkyl and heteroaryl is optionallysubstituted with one more substituents, wherein each substituent is,independently, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, cyano,nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂,amidino, guanidino, aminosulfonyl, aminoalkoxy, aminoalkythio, loweracylamino, or benzyloxycarbonyl; and wherein the substituted aryl groupis substituted with one more substituents, wherein each substituent is,independently, amino, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein pis 1 to 5, —N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl,aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl. Insome embodiments, each V is, independently, hydroxy, amino, alkylamino,dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂,guanidino, amidino, ureido, carbamoyl, —C(═O)OH, —C(═O)OR^(c),—C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH, NR^(d)R^(e), asubstituted aryl group, heterocycloalkyl, or heteroaryl, wherein each ofthe heterocycloalkyl and heteroaryl is optionally substituted with onemore substituents, wherein each substituent is, independently, amino,cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl, aminoalkoxy,aminoalkythio, lower acylamino, or benzyloxycarbonyl; and wherein thesubstituted aryl group is substituted with one more substituents,wherein each substituent is, independently, amino, cyano, nitro,hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, amidino,guanidino, aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino,or benzyloxycarbonyl.

In some embodiments, each V is, independently, hydroxy, amino,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, carbamoyl, —C(═O)NH—OH,—O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, NR^(d)R^(e), heterocycloalkyl, orheteroaryl, wherein each of the heterocycloalkyl and heteroaryl isoptionally substituted with one more substituents, wherein eachsubstituent is, independently, alkyl, haloalkyl, alkoxy, haloalkoxy,amino, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl, aminoalkoxy,aminoalkythio, lower acylamino, or benzyloxycarbonyl.

In some embodiments, each V is, independently, hydroxy, amino,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, carbamoyl, —C(═O)NH—OH,—O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, NR^(d)R^(e), heterocycloalkyl, orheteroaryl, wherein each of the heterocycloalkyl and heteroaryl isoptionally substituted with one more substituents, wherein eachsubstituent is, independently, amino, cyano, nitro, hydroxy,—NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, amidino, guanidino,aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, orbenzyloxycarbonyl.

In some embodiments, each V is, independently, hydroxy, amino,alkylamino, arylamino, heteroarylamino, ureido, carbamoyl, —C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH, a3-8 membered heterocycloalkyl, a 5- to 10-membered heteroaryl, or a 6-to 10-membered substituted aryl, wherein the substituted aryl issubstituted with one or more substituents, wherein each substituent is,independently, OH, amino, hydroxylalkyl, or aminoalkyl, and wherein eachof the 3-8 membered heterocycloalkyl and the 5- to 10-memberedheteroaryl is optionally substituted with one or more substituents,wherein each substituent is, independently, alkyl, haloalkyl, alkoxy,haloalkoxy, amino, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1to 5, —N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl, aminoalkoxy,aminoalkythio, lower acylamino, or benzyloxycarbonyl.

In some embodiments, each V is, independently, hydroxy, amino,alkylamino, arylamino, heteroarylamino, ureido, carbamoyl, —C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH, a3-8 membered heterocycloalkyl, a 5- to 10-membered heteroaryl, or a 6-to 10-membered substituted aryl, wherein the substituted aryl issubstituted with one or more substituents, wherein each substituent is,independently, OH, amino, hydroxylalkyl, or aminoalkyl.

In some embodiments, each V is, independently, amino, heteroarylamino,ureido, carbamoyl, C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂,—NH—S(═O)₂OH, S(═O)₂OH, aziridinyl, azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholino, azepanyl, azocanyl, tetrazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, imidazolyl, pyridinyl, indolyl, ora substituted phenyl, wherein the substituted phenyl is substituted withone or more substituents, wherein each substituent is, independently, OHor amino.

In some embodiments, each V is, independently, amino, alkylamino,dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂,guanidino, amidino, ureido, heterocycloalkyl, or heteroaryl, whereineach of the heterocycloalkyl and heteroaryl is optionally substitutedwith one more substituents, wherein each substituent is, independently,amino, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl, aminoalkoxy,aminoalkythio, lower acylamino, or benzyloxycarbonyl.

In some embodiments, each V is, independently, amino, alkylamino,dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂,guanidino, amidino, ureido, pyrrodinyl, piperidinyl, piperazinyl,4-methylpiperazinyl, pyridinyl, pyrimidinyl, pyrazinyl, or indolyl. Insome embodiments, each V is, independently, amino, alkylamino,dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂,guanidino, amidino, ureido, or indolyl.

In some embodiments, each PL is, independently, halo,hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5′))_(q2PL)—V.

In some embodiments, each PL group is, independently, halo,—(CH₂)_(pPL)—V, O—(CH₂)_(pPL)—V, or S—(CH₂)_(pPL)—V; each pPL is aninteger from 0 to 5; and each V is, independently, hydroxy, amino, halo,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is to 5,—N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, carbamoyl, —C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH,NR^(d)R^(e), a substituted aryl group, heterocycloalkyl, or heteroaryl,wherein each of the heterocycloalkyl and heteroaryl is optionallysubstituted with one more substituents, wherein each substituent is,independently, amino, halo, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl,aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl; andwherein the substituted aryl group is substituted with one moresubstituents, wherein each substituent is, independently, amino, halo,cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl, aminoalkoxy,aminoalkythio, lower acylamino, or benzyloxycarbonyl.

In some embodiments, each PL group is, independently, halo,—(CH₂)_(pPL)—V, O—(CH₂)_(pPL)—V, or S—(CH₂)_(pPL)—V; each pPL is aninteger from 0 to 5; and each V is, independently, hydroxy, amino,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, carbamoyl, —C(═O)NH—OH,—O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, NR^(d)R^(e), heterocycloalkyl, orheteroaryl, wherein each of the heterocycloalkyl and heteroaryl isoptionally substituted with one more substituents, wherein eachsubstituent is, independently, amino, halo, cyano, nitro, hydroxy,—NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, amidino, guanidino,aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, orbenzyloxycarbonyl.

In some embodiments, each NPL group is, independently, —B(OR⁴)₂, R^(4′),or OR^(4′), R⁴ and R^(4′) are each, independently, alkyl, alkenyl,alkynyl, cycloalkyl, or aryl, each is optionally substituted with one ormore substitutents, wherein each substituent is, independently, alkyl,halo, or haloalkyl; each PL group is, independently, halo,—(CH₂)_(pPL)—V, O—(CH₂)_(pPL)—V, or S—(CH₂)_(pPL)—V; each pPL is aninteger from 0 to 5; and each V is, independently, hydroxy, amino,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, carbamoyl, —C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH,NR^(d)R^(e), a substituted aryl group, heterocycloalkyl, or heteroaryl,wherein each of the heterocycloalkyl and heteroaryl is optionallysubstituted with one more substituents, wherein each substituent is,independently, amino, halo, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl,aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl; andwherein the substituted aryl group is substituted with one moresubstituents, wherein each substituent is, independently, amino, halo,cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl, aminoalkoxy,aminoalkythio, lower acylamino, or benzyloxycarbonyl.

In some embodiments, each X is, independently, NR⁸; each Y is C═O; A₁and A₂ are each, independently, phenyl or a 6-membered heteroaryl, eachoptionally substituted with one or more substituents, wherein eachsubstituent is, independently, alkyl, haloalkyl, halo, —O-alkyl,O—(CH₂)_(pPL)—V, or S—(CH₂)_(pPL)—V; R¹ is —C(═O)—(CH₂)_(pPL)—V or—C(═O)—(CH₂)_(pNPL)—R^(4′); R² is R¹; R^(4′) is H or alkyl; and each Vis, independently, hydroxy, amino, alkylamino, dialkylamino,—NH(CH₂)_(p)NH₂ wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, guanidino, amidino,ureido, carbamoyl, heterocycloalkyl, or heteroaryl.

In some embodiments, each X is NH; each Y is C═O; each A₁ is,independently, phenyl optionally substituted with one or twosubstituents, wherein each substituent is, independently, haloalkyl,halo, —O-alkyl, O—(CH₂)_(pPL)—V, or S—(CH₂)_(pPL)—V; A₂ is phenyl or a6-membered heteroaryl, each optionally substituted with one or twosubstituents, wherein each substituent is, independently, —O-alkyl; R¹is —C(═O)—(CH₂)_(pPL)—V; R² is R¹; and each V is, independently,hydroxy, amino, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1to 5, —N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, carbamoyl,heterocycloalkyl, or heteroaryl.

In some embodiments, each X is NH; each Y is C═O; each A₁ is,independently, phenyl optionally substituted with one or twosubstituents, wherein each substituent is, independently, haloalkyl,O—(CH₂)_(pPL)—V, or S—(CH₂)_(pPL)—V; A₂ is phenyl or pyrimidinyl, eachoptionally substituted with one or two substituents, wherein eachsubstituent is, independently, —O-alkyl; R¹ is —C(═O)—(CH₂)_(pPL)—V; R²is R¹; and each V is, independently, amino, alkylamino, dialkylamino,—NH(CH₂)_(p)NH₂ wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, guanidino, amidino,ureido, carbamoyl, or indolyl.

In some embodiments, the moiety of —Y-A₂-Y— is a moiety of FormulaXIX-1, XIX-2, or XIX-3:

wherein each R^(12a) is, independently, a PL group or an NPL group; andt2 is 0, 1, or 2.

In some embodiments, the moiety of —Y-A₂-Y— is a moiety of Formula XIX-1or XIX-2; and each R^(12a) is, independently, halo, alkyl, alkoxy,haloalkyl, haloalkoxy, —(CH₂)_(pPL)—V, —O(CH₂)_(pPL)—V, or—S(CH₂)_(pPL)—V, wherein pPL is an integer from 1 to 5.

In some embodiments, each R^(12a) is, independently, halo, alkyl,alkoxy, haloalkyl, or haloalkoxy. In some embodiments, each R^(12a) is,independently, alkoxy. In some embodiments, each R^(12a) is methoxy.

In some embodiments, the moiety of —Y-A₂-Y— is a moiety of Formula XIX-1or XIX-2; and t2 is 2.

In some embodiments, each R^(12a) is, independently, alkoxy. In someembodiments, each R^(12a) is methoxy.

In some embodiments, the moiety of —Y-A₂-Y— is a moiety of FormulaXIX-1, and the moiety of Formula XIX-1 is a moiety of Formula XIX-1a:

In some embodiments, each of the moiety of —X-A₁-X— is, independently, amoiety of Formula XIX-B:

wherein each R^(13a) is, independently, a PL group or an NPL group; andt3 is 0, 1, or 2.

In some embodiments, wherein each of the moiety of —X-A₁-X— is,independently, a moiety of Formula XIX-C:

wherein each of R^(13a-1) and R^(13a-2) is, independently, H, a PLgroup, or an NPL group.

In some embodiments, each of R^(13a-1) and R^(13a-2) are, independently,a PL group or an NPL group. In some embodiments, each of R^(13a-1) andR^(13a-2) are, independently, halo, alkyl, haloalkyl, —O(CH₂)_(pPL)—V,or —S(CH₂)_(pPL)—V, wherein pPL is an integer from 1 to 5. In someembodiments, each of R^(13a-1) and R^(13a-2) are, independently,haloalkyl or —S(CH₂)_(pPL)—V, wherein pPL is an integer from 1 to 5.

In some embodiments, each A₂ is, independently, optionally substitutedarylene or optionally substituted heteroarylene, and each A₁ is,independently, optionally substituted C₃ to C₈ cycloalkyl, wherein A₁and A₂ are each, independently, optionally substituted with one or morePL group(s), one or more NPL group(s), or a combination of one or morePL group(s) and one or more NPL group(s); R¹ is —Y-A₂-Y—R²; and each R²is, independently, hydrogen, a PL group, or an NPL group. In someembodiments, each X is NH; and each Y is C═O. In some embodiments, m is1 or 2.

In some embodiments, each A₂ is, independently, optionally substitutedphenyl, and each A₁ is, independently, optionally substituted C₃-C₈cycloalkyl, wherein A₁ and A₂ are each, independently, optionallysubstituted with one or more PL group(s), one or more NPL group(s), or acombination of one or more PL group(s) and one or more NPL group(s); R¹is —Y-A₂-Y—R²; and each R² is, independently, hydrogen, a PL group, oran NPL group. In some embodiments, each X is NH; and each Y is C═O. Insome embodiments, m is 1 or 2.

In some embodiments, each A₁ is, independently, C₅-C₆ cycloalkyl; eachA₂ is, independently, phenyl optionally substituted with one or more PLgroup(s), one or more NPL group(s), or a combination of one or more PLgroup(s) and one or more NPL group(s); R¹ is —Y-A₂-Y—R²; and each R² is,independently, hydrogen, a PL group, or an NPL group. In someembodiments, each X is NH; and each Y is C═O. In some embodiments, m is1 or 2.

In some embodiments, each NPL group is, independently, —B(OR⁴)₂, R^(4′),or OR^(4′); R⁴ and R^(4′) are each, independently, alkyl, alkenyl,alkynyl, cycloalkyl, or aryl, each is optionally substituted with one ormore substitutents, wherein each substituent is, independently, alkyl,halo, or haloalkyl; each PL group is, independently, halo,—(CH₂)_(pPL)—V, O—(CH₂)_(pPL)—V, or S—(CH₂)_(pPL)—V; each pPL is aninteger from 0 to 5; and each V is, independently, hydroxy, amino,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, carbamoyl, —C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH,NR^(d)R^(e), a substituted aryl group, heterocycloalkyl, and heteroaryl,wherein each of the heterocycloalkyl and heteroaryl is optionallysubstituted with one more substituents, wherein each substituent is,independently, amino, halo, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl,aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl; andwherein the substituted aryl group is substituted with one moresubstituents, wherein each substituent is, independently, amino, halo,cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl, aminoalkoxy,aminoalkythio, lower acylamino, or benzyloxycarbonyl. In someembodiments, each X is NH; and each Y is C═O. In some embodiments, m is1 or 2.

In some embodiments, each A₁ is C₆ cycloalkyl; each A₂ is,independently, phenyl optionally substituted with one or moresubstituents, wherein each substituent is, independently, haloalkyl,halo, —O-alkyl, O—(CH₂)_(pPL)—V, or S—(CH₂)_(pPL)—V; R¹ is —Y-A₂-Y—R²;each R² is, independently, NH—(CH₂)_(pPL)—V; and each V is,independently, hydroxy, amino, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido,carbamoyl, heterocycloalkyl, or heteroaryl. In some embodiments, each Xis NH; and each Y is C═O. In some embodiments, m is 1 or 2.

In some embodiments, each A₁ is C₆ cycloalkyl; each A₂ is,independently, phenyl optionally substituted with one or moresubstituents, wherein each substituent is, independently, haloalkyl,—O-alkyl, O—(CH₂)_(pPL)—V, or S—(CH₂)_(pPL)—V; R¹ is —Y-A₂-Y—R²; each

R² is, independently, NH—(CH₂)_(pPL)—V; and each V is, independently,amino, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, carbamoyl, or indolyl. Insome embodiments, each X is NH; and each Y is C═O. In some embodiments,m is 1 or 2.

In some embodiments, each of the moiety of —Y-A₂-Y— is a moiety ofFormula XIX-1 or XIX-1a:

wherein each R^(12a) is, independently, a PL group or an NPL group; andt2 is 0, 1, or 2; and each of the moiety of —X-A₁-X— is, independently,a moiety of Formula XIX-D:

wherein each R^(14a) is, independently, a PL group or an NPL group. Insome embodiments, each of the moiety of —Y-A₂-Y— is a moiety of FormulaXIX-1a, and each of the moiety of —X-A₁-X— is a moiety of Formula XIX-Dwherein t4 is 0. In some embodiments, each R^(12a) is, independently,halo, alkyl, alkoxy, haloalkyl, haloalkoxy, —(CH₂)_(pPL)—V,—O(CH₂)_(pPL)—V, or —S(CH₂)_(pPL)—V, wherein pPL is an integer from 1 to5. In some embodiments, each R^(12a) is, independently, alkoxy or—O(CH₂)_(pPL)—V, wherein pPL is an integer from 1 to 5. In someembodiments, R¹ is —Y-A₂-Y—R²; and each R² is, independently, hydrogen,a PL group, or an NPL group. In some embodiments, m is 1, 2, or 3. Insome embodiments, m is 1 or 2.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound chosenfrom:

or a pharmaceutically acceptable salt thereof.

The compounds of Formula XIX or XIXa (such as the polymers andoligomers) or pharmaceutically acceptable salts thereof useful in thepresent invention can be made, for example, by methods described in U.S.Patent Application Publication No. 2006-0041023, U.S. Pat. No.7,173,102, International Publication No. WO 2004/082643, InternationalPublication No. WO2006093813, and U.S. Patent Application Publication2010-0081665. In some embodiments, the compounds of Formula XIX or XIXa(such as the polymers and oligomers) or pharmaceutically acceptablesalts thereof useful in the present invention can be selected from thosedescribed in U.S. Patent Application Publication No. 2006-0041023, U.S.Pat. No. 7,173,102, International Publication No. WO 2004/082643,International Publication No. WO2006093813, and U.S. Patent ApplicationPublication 2010-0081665.

In some embodiments, the compound(s) useful in the method of presentinvention can be chosen from one or more of the compounds (i.e.,genuses, sub-genuses, and species) disclosed in U.S. Patent ApplicationPublication No. 2006-0041023, U.S. Pat. No. 7,173,102, InternationalPublication No. WO 2005/123660, International Publication No. WO2004/082643, International Publication No. WO 2006/093813, and U.S.Patent Application Publication 2010-0081665, each of which is herebyincorporated by reference in its entirety.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XX:

or a pharmaceutically acceptable salt thereof,wherein:

each X is, independently, NR⁸;

each Y is C═O;

each R⁸ is, independently, hydrogen or alkyl;

each A₂ is optionally substituted arylene or optionally substitutedheteroarylene, and each A₁ is —(CH₂)_(q)—, wherein q is 1 to 7, whereinA₁ and A₂ are each, independently, optionally substituted with one ormore PL group(s), one or more NPL group(s), or a combination of one ormore PL group(s) and one or more NPL group(s);

R² and R^(2a) are each, independently, hydrogen, a PL group, an NPLgroup or —X-A₁-Y—R¹¹, wherein R¹¹ is hydrogen, a PL group, or an NPLgroup;

L¹ is C₁₋₁₀ alkylene optionally substituted with one or moresubstitutents, wherein each substituent is, independently, alkyl, halo,haloalkyl, aminoalkyl, hydroxylalkyl, V, or —(CH₂)_(pPL)—V, wherein pPLis an integer from 1 to 5;

each NPL group is, independently, —B(OR⁴)₂ or—(NR^(3′))_(q1NPL)—U^(NPL)-LK^(NPL)—(NR^(3″))_(q2NPL)—R^(4′), wherein:

R³, R^(3′), and R^(3″) are each, independently, hydrogen, alkyl, oralkoxy;

R⁴ and R^(4′) are each, independently, hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, or heteroaryl, wherein each of the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more substitutents, wherein each substituent is,independently, alkyl, halo, or haloalkyl;

each U^(NPL) is, independently, absent or O, S, S(═O), S(═O)₂, NR³,—C(═O)—, —C(═O)—NR³—, —C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—,—C(═N—N(R³)₂)—, —C(═NR³)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—,—S—C═N—, or —C(═O)—NR³—O—, wherein groups with two chemicallynonequivalent termini can adopt both possible orientations;

each LK^(NPL) is, independently, —(CH₂)_(pNPL)— and C₂₋₈ alkenylenyl,wherein each of the —(CH₂)_(pNPL) and C₂₋₈ alkenylenyl is optionallysubstituted with one or more substituents, wherein each substituent is,independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;

each pNPL is, independently, an integer from 0 to 8;

q1NPL and q2NPL are each, independently, 0, 1, or 2;

each PL group is, independently, halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, or—(NR^(5′))_(q1PL)—U^(PL)-LK^(PL)—(NR^(5″))_(q2PL)—V, wherein:

R⁵, R^(5′), and R^(5″) are each, independently, hydrogen, alkyl, oralkoxy;

each U^(PL) is, independently, absent or O, S, S(═O), S(═O)₂, NR⁵,—C(═O)—, —C(═O)—NR⁵—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—,—C(═N—N(R⁵)₂)—, —C(═NR⁵)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—,—S—C═N—, or —C(═O)—NR⁵—O—, wherein groups with two chemicallynonequivalent termini can adopt either of the two possible orientations;

each V is, independently, nitro, cyano, amino, halo, hydroxy, alkoxy,alkylthio, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to5, —C(═O)NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—C(═O)NH(CH₂)_(p)NHC(═NH)NH₂ wherein p is 1 to 5,—C(═O)NH(CH₂)_(p)NHC(═O)NH₂ wherein p is 1 to 5, —NHC(═O)-alkyl,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, ureido, carbamoyl,—C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH,S(═O)₂OH, NR^(d)R^(e), semicarbazone, aryl, cycloalkyl,heterocycloalkyl, or heteroaryl, wherein each of the aryl and cycloalkylis substituted with one or more substitutents, wherein each of theheterocycloalkyl and heteroaryl is optionally substituted with one ormore substituents, and wherein each of the substituents for the aryl,cycloalkyl, heterocycloalkyl, and heteroaryl is, independently, nitro,cyano, amino, halo, hydroxy, alkoxy, alkylthio, alkylamino,dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂,diazamino, amidino, guanidino, ureido, carbamoyl, —C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH,NR^(d)R^(e), semicarbazone, aminosulfonyl, aminoalkoxy, aminoalkythio,lower acylamino, or benzyloxycarbonyl;

each R^(e) is, independently, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, eachoptionally substituted by one or more substitutents, wherein eachsubstituent is, independently, OH, amino, halo, C₁₋₆ alkyl,C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl,or heterocycloalkyl;

R^(d) and R^(e) are, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl,wherein each of the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionallysubstituted by OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, orheterocycloalkyl;

or R^(d) and R^(e) together with the N atom to which they are attachedform a 4-, 5-, 6-, 7-, or 8-membered heterocycloalkyl;

each LK^(PL) is, independently, —(CH₂)_(pPL)— or C₂₋₈ alkenylenyl,wherein each of the —(CH₂)_(pNPL)— and C₂₋₈ alkenylenyl is optionallysubstituted with one or more substituents, wherein each substituent is,independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;

each pPL is, independently, an integer from 0 to 8;

q1PL and q2PL are each, independently, 0, 1, or 2;

m11 is an integer from 1 to about 20; and

m12 is an integer from 1 to about 20.

In some embodiments, each moiety of X-A₁-Y—X-A₂-Y is, independently, amoiety of:

each R⁹ is, independently, H, a PL group, or an NPL group; each R¹⁰ is,independently, H, a PL group, or an NPL group; each R^(11a) is,independently, a PL group or an NPL group; and each t1 is independently0, 1, or 2.

In some embodiments, each R⁹ is, independently, a PL group or an NPLgroup; and each R¹⁰ is H. In some embodiments, each R⁹ is,independently, alkyl or (CH₂)_(pPL)—V where pPL is an integer from 1 to5; each R¹⁰ is H; and each R^(11a) is, independently, halo, alkyl,alkoxy, haloalkyl, haloalkoxy, —(CH₂)_(pPL)—V, —O(CH₂)_(pPL)—V, or—S(CH₂)_(pPL)—V, wherein pPL is an integer from 1 to 5.

In some embodiments, each R⁹ is, independently, alkyl, —(CH₂)—V,—(CH₂)₂—V, —(CH₂)₃—V, —(CH₂)₄—V, or —(CH₂)₅—V; each R¹⁰ is H; each V is,independently, hydroxyl, amino, heteroarylamino, ureido, guanidino,carbamoyl, C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂,—NH—S(═O)₂OH, S(═O)₂OH, aziridinyl, azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholino, azepanyl, azocanyl, tetrazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, imidazolyl, pyridinyl, indolyl, ora substituted phenyl, wherein the substituted phenyl is substituted withone or more substituents, wherein each substituent is, independently, OHor amino; and each R^(11a) is, independently, alkoxy.

In some embodiments, each R⁹ is, independently, CH₃, —(CH₂)—V,—(CH₂)₂—V, —(CH₂)₃—V, —(CH₂)₄—V, and —(CH₂)₅—V; each R¹⁰ is H; each Vis, independently, amino, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, orindolyl; and each R^(11a) is, independently, alkoxy.

In some embodiments, each R⁹ is, independently, CH₃, —(CH₂)—V,—(CH₂)₂—V, —(CH₂)₃—V, —(CH₂)₄—V, and —(CH₂)₅—V; each R¹⁰ is H; each Vis, independently, amino, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, orindolyl; and each R^(11a) is methoxy.

In some embodiments, each moiety of X-A₁-Y—X-A₂-Y is, independently, amoiety of:

In some embodiments, R² and R^(2a) are each, independently, NH₂,amidino, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,or —NH—(CH₂)_(pPL)—V¹⁰, wherein V is amino, alkylamino, dialkylamino,—NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, guanidino, amidino,ureido, or carbamoyl; and L¹ is C₅₋₁₀alkylene optionally substitutedwith one or more substitutents, wherein each substituent is,independently, alkyl, halo, haloalkyl, aminoalkyl, or hydroxylalkyl.

In some embodiments, each of R² and R^(2a) is NH₂; and L¹ isC₅₋₁₀alkylene, such as, for example C₇₋₁₀alkylene or C₇₋₉alkylene.

In some embodiments, m11 is an integer from 1 to about 10; and m12 is aninteger from 1 to about 10. In some embodiments, m11 is an integer from3 to 7; and m12 is an integer from 3 to 7. In some embodiments, m11 isan integer from 3 to 5; and m12 is an integer from 3 to 5.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XXI:

R¹-[-X-A₁-Y—X-A₂-Y-]_(m13)-X-L¹-Y-[-X-A₁-Y—X-A₂-Y-]_(m14)—R²  XXI

or a pharmaceutically acceptable salt thereof,wherein:

each X is, independently, NR⁸;

each Y is C═O;

each R⁸ is, independently, hydrogen or alkyl;

each A₂ is optionally substituted arylene or optionally substitutedheteroarylene, and each A₁ is —(CH₂)_(q)—, wherein q is 1 to 7, whereinA₁ and A₂ are each, independently, optionally substituted with one ormore PL group(s), one or more NPL group(s), or a combination of one ormore PL group(s) and one or more NPL group(s);

R¹ is hydrogen, a PL group, or an NPL group, and R^(e) is —X-A₁-Y—R¹¹,wherein R¹¹ is hydrogen, a PL group, or an NPL group; or

R¹ and R² are each, independently, hydrogen, a PL group, or an NPLgroup; or

R¹ and R² together are a single bond; or

R¹ is —Y-A₂-X—R¹², wherein R¹² is hydrogen, a PL group, or an NPL group,and R² is hydrogen, a PL group, or an NPL group;

L¹ is C₁₋₁₀alkylene optionally substituted with one or moresubstitutents, wherein each substituent is, independently, alkyl, halo,haloalkyl, aminoalkyl, hydroxylalkyl, V, or —(CH₂)_(pPL)—V wherein pPLis an integer from 1 to 5;

each V is, independently, hydroxy, amino, alkylamino, dialkylamino,—NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —C(═O)NH(CH₂)_(p)NH₂ wherein p is 1to 5, —C(═O)NH(CH₂)_(p)NHC(═NH)NH₂ wherein p is 1 to 5,—C(═O)NH(CH₂)_(p)NHC(═O)NH₂ wherein p is 1 to 5, —NHC(═O)-alkyl,—N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, carbamoyl, —C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH,NR^(d)R^(e), a substituted aryl group, heterocycloalkyl, or heteroaryl,wherein each of the heterocycloalkyl and heteroaryl is optionallysubstituted with one more substituents, wherein each substituent is,independently, amino, halo, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl,aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl; andwherein the substituted aryl group is substituted with one moresubstituents, wherein each substituent is, independently, amino, halo,cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl, aminoalkoxy,aminoalkythio, lower acylamino, or benzyloxycarbonyl;

each NPL group is, independently, —B(OR⁴)₂ or—(NR^(3′))_(q1NPL)—U^(NPL)-LK^(NPL)—(NR^(3″))_(q2NPL)—R^(4′), wherein:

R³, R^(3′), and R^(3″) are each, independently, hydrogen, alkyl, oralkoxy;

R⁴ and R^(4′) are each, independently, hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, or heteroaryl, wherein each of the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more substitutents, wherein each substituent is,independently, alkyl, halo, or haloalkyl;

each U^(NPL) is, independently, absent or O, S, S(═O), S(═O)₂, NR³,—C(═O)—, —C(═O)—NR³—, —C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—,—C(═N—N(R³)₂)—, —C(═NR³)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—,—S—C═N—, or —C(═O)—NR³—O—, wherein groups with two chemicallynonequivalent termini can adopt both possible orientations;

each LK^(NPL) is, independently, —(CH₂)_(pNPL)— or C₂₋₈ alkenylenyl,wherein each of the —(CH₂)_(pNPL) and C₂₋₈ alkenylenyl is optionallysubstituted with one or more substituents, wherein each substituent is,independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;

each pNPL is, independently, an integer from 0 to 8;

q1NPL and q2NPL are each, independently, 0, 1, or 2;

each PL group is, independently, halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, or—(NR⁵)_(q1PL)—U^(PL)-LK^(PL)—(NR⁵)_(q2PL)—V, wherein:

R⁵, R^(5′), and R^(5″) are each, independently, hydrogen, alkyl, oralkoxy;

each U^(PL) is, independently, absent or O, S, S(═O), S(═O)₂, NR⁵,—C(═O)—, —C(═O)—NR⁵—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—,—C(═N—N(R⁵)₂)—, —C(═NR⁵)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—,—S—C═N—, or —C(═O)—NR⁵—O—, wherein groups with two chemicallynonequivalent termini can adopt either of the two possible orientations;

each R^(c) is, independently, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, eachoptionally substituted by one or more substitutents, wherein eachsubstituent is, independently, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, orheterocycloalkyl;

R^(d) and R^(e) are, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl,wherein each of the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl isoptionally substituted by OH, amino, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl,C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkylor heterocycloalkyl;

or R^(d) and R^(e) together with the N atom to which they are attachedform a 4-, 5-, 6-, 7-, or 8-membered heterocycloalkyl;

each LK^(PL) is, independently, —(CH₂)_(pPL)— or C₂₋₈ alkenylenyl,wherein each of the —(CH₂)_(pNPL)— and C₂₋₈ alkenylenyl is optionallysubstituted with one or more substituents, wherein each substituent is,independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;

each pPL is, independently, an integer from 0 to 8;

q1PL and q2PL are each, independently, 0, 1, or 2;

m13 is an integer from 1 to about 10; and

m14 is an integer from 1 to about 10.

In some embodiments, each moiety of X-A₁-Y—X-A₂-Y is, independently, amoiety of:

each R⁹ is, independently, H, a PL group, or an NPL group; each R¹⁰ is,independently, H, a PL group, or an NPL group; each R^(11a) is,independently, a PL group or an NPL group; and each t1 is independently0, 1, or 2.

In some embodiments, each R⁹ is, independently, a PL group or an NPLgroup; and each R¹⁰ is H. In some embodiments, each R⁹ is,independently, alkyl or (CH₂)_(pPL)—V wherein pPL is an integer from 1to 5; each R¹⁰ is H; and each R^(11a) is, independently, halo, alkyl,alkoxy, haloalkyl, haloalkoxy, —(CH₂)_(pPL)—V, —O(CH₂)_(pPL)—V, or—S(CH₂)_(pPL)—V, wherein pPL is an integer from 1 to 5.

In some embodiments, each R⁹ is, independently, alkyl, —(CH₂)—V,—(CH₂)₂—V, —(CH₂)₃—V, —(CH₂)₄—V, or —(CH₂)₅—V; each R¹⁰ is H; each V is,independently, hydroxyl, amino, heteroarylamino, ureido, guanidino,carbamoyl, C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂,—NH—S(═O)₂OH, S(═O)₂OH, aziridinyl, azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholino, azepanyl, azocanyl, tetrazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, imidazolyl, pyridinyl, indolyl, ora substituted phenyl, wherein the substituted phenyl is substituted withone or more substituents, wherein each substituent is, independently, OHor amino; and each R^(11a) is, independently, alkoxy.

In some embodiments, each R⁹ is, independently, CH₃, —(CH₂)—V,—(CH₂)₂—V, —(CH₂)₃—V, —(CH₂)₄—V, or —(CH₂)₅—V; each R¹⁰ is H; each V is,independently, amino, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ whereinp is 1 to 5, —N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, or indolyl; andeach R^(11a) is, independently, alkoxy.

In some embodiments, each R⁹ is, independently, CH₃, —(CH₂)—V,—(CH₂)₂—V, —(CH₂)₃—V, —(CH₂)₄—V, or —(CH₂)₅—V; each R¹⁰ is H; each V is,independently, amino, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ whereinp is 1 to 5, —N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, or indolyl; andeach R^(11a) is methoxy.

In some embodiments, each moiety of X-A₁-Y—X-A₂-Y is, independently, amoiety of:

In some embodiments, the moiety of —X-L¹-Y— is a moiety of—NH-L¹-C(═O)—; R¹ is H or alkyl; R² is NH₂, amidino, alkylamino,dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, or—NH—(CH₂)_(pPL)—V¹⁰, wherein V¹⁰ is amino, alkylamino, dialkylamino,—NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, guanidino, amidino,ureido, or carbamoyl; and L¹ is C₁₋₃alkylene optionally substituted withone or more substitutents, wherein each substituent is, independently,alkyl, halo, haloalkyl, aminoalkyl, hydroxylalkyl, V¹¹, or—(CH₂)_(pPL)—V¹¹ wherein pPL is an integer from 1 to 5, wherein each V¹¹is, independently, amino, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, orcarbamoyl.

In some embodiments, the moiety of —X-L¹-Y— is a moiety of—NH-L¹-C(═O)—; R¹ is H; R² is NH₂; and L¹ is C₁alkylene optionallysubstituted with one or more substitutents, wherein each substituent is,independently, alkyl, halo, haloalkyl, aminoalkyl, hydroxylalkyl, V¹¹,or —(CH₂)_(pPL)—V¹¹ wherein pPL is an integer from 1 to 5, wherein V¹¹is amino, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, or carbamoyl.

In some embodiments, m13 is an integer from 1 to about 5; and m14 is aninteger from 1 to about 5. In some embodiments, m13 is an integer from 1to 3; and m12 is an integer from 1 to 3. In some embodiments, the sum ofm13 and m14 is an integer from 3 to 5. In some embodiments, the sum ofm13 and m14 is 4.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XXII:

R¹-[-X-A₁-X—Z—Y-A₂-Y—Z]_(m)—R²  XXII

or a pharmaceutically acceptable salt thereof,wherein:

X is NR⁸, —NR⁸NR⁸—, C═O, or 0;

Y is NR⁸, —NR⁸NR⁸—, C═O, S, or O;

R⁸ is hydrogen or alkyl;

Z is C═O, C═S, O═S═O, —NR⁸NR⁸—, or —C(═O)C(═O)—;

A₁ and A₂ are, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein A₁ and A₂ are,independently, optionally substituted with one or more polar (PL)group(s), one or more non-polar (NPL) group(s), or a combination of oneor more polar (PL) group(s) and one or more non-polar (NPL) group(s);

R¹ is

-   -   (i) hydrogen, a polar group (PL), or a non-polar group (NPL),        and R² is —X-A₁-X—R¹, wherein A₁ is as defined above and is        optionally substituted with one or more polar (PL) group(s), one        or more non-polar (NPL) group(s), or a combination of one or        more polar (PL) group(s) and one or more non-polar (NPL)        group(s); or    -   (ii) hydrogen, a polar group (PL), or a non-polar group (NPL),        and R² is —X-A₁-X—Z—Y-A₂-Y—R¹, wherein A₁ and A₂ are as defined        above, and each of which is optionally substituted with one or        more polar (PL) group(s), one or more non-polar (NPL) group(s),        or a combination of one or more polar (PL) group(s) and one or        more non-polar (NPL) group(s); or    -   (iii) hydrogen, a polar group (PL), or a non-polar group (NPL),        and R² is —X-A′-X—R¹, wherein A′ is aryl or heteroaryl and is        optionally substituted with one or more polar (PL) group(s), one        or more non-polar (NPL) group(s), or a combination of one or        more polar (PL) group(s) and one or more non-polar (NPL)        group(s); or    -   (iv) hydrogen, a polar group (PL), or a non-polar group (NPL),        and R² is —X-A₁-X—Z—Y-A′-Y—R¹, wherein A₁ is as defined above,        A′ is aryl or heteroaryl, and each of A₁ and A′ is optionally        substituted with one or more polar (PL) group(s), one or more        non-polar (NPL) group(s), or a combination of one or more polar        (PL) group(s) and one or more non-polar (NPL) group(s); or    -   (v) —Z—Y-A¹ and R² is hydrogen, a polar group (PL), or a        non-polar group (NPL), wherein A′ is aryl or heteroaryl and is        optionally substituted with one or more polar (PL) group(s), one        or more non-polar (NPL) group(s), or a combination of one or        more polar (PL) group(s) and one or more non-polar (NPL)        group(s); or    -   (vi) —Z—Y-A′, and R² is —X-A″, wherein A′ and A″ are,        independently, aryl or heteroaryl, and each of A′ and A″ is        optionally substituted with one or more polar (PL) group(s), one        or more non-polar (NPL) group(s), or a combination of one or        more polar (PL) group(s) and one or more non-polar (NPL)        group(s); or    -   (vii) R¹ and R² are, independently, a polar group (PL) or a        non-polar group (NPL); or    -   (viii) R¹ and R² together form a single bond; NPL is a nonpolar        group independently selected from —B(OR⁴)₂ and        —(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R^(4′),        wherein:

R³, R^(3′), and R^(3″) independently, selected from hydrogen, alkyl, andalkoxy;

R⁴ and R^(4′) are, independently, selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which isoptionally substituted with one or more alkyl or halo groups;

U^(NPL) is absent or selected from O, S, S(═O), S(═O)₂, NR³, —C(═O)—,—C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³⁰—, —R³S—, —S—C═N—, and—C(═O)—NR³—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

the —(CH₂)_(pNPL)— alkylene chain is optionally substituted with one ormore amino or hydroxy groups, or is unsaturated;

pNPL is 0 to 8;

q1NPL and q2NPL are, independently, 0, 1, or 2;

PL is a polar group selected from halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, and—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5′))_(q2PL)—V,

wherein:

R⁵, R^(5′), and R^(5″) are, independently, selected from hydrogen,alkyl, and alkoxy;

U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵, —C(═O)—,—C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—, —S—C═N—, and—C(═O)—NR⁵—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

V is selected from nitro, cyano, amino, hydroxy, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 4,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, guanyl, semicarbazone,aryl, heterocycle, and heteroaryl, any of which is optionallysubstituted with one or more of amino, halo, cyano, nitro, hydroxy,—NH(CH₂)_(p)NH₂ wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, amidino, guanidino,guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, orbenzyloxycarbonyl;

the —(CH₂)_(pPL)— alkylene chain is optionally substituted with one ormore amino or hydroxy groups, or is unsaturated;

pPL is 0 to 8;

q1PL and q2PL are, independently, 0, 1, or 2; and

m is 1 to about 20.

In some embodiments, the compound is a compound of Formula XXIIa,Formula XXIIb, or Formula XXIIc:

R¹—X-A₁-X—Z—Y-A₂-Y—R²  XXIIa

R¹—X-A₁-X—Z—Y-A₂-Y—Z—X-A₁-X—R²  XXIIb

R¹—X-A₁-X—Z—Y-A₂-Y—Z—X-A₁-X—Z—Y-A₂-Y—R²  XXIIc

wherein: X is NR⁸, —NR⁸NR⁸—, C═O, or O; Y is NR⁸, —NR⁸NR⁸—, C═O, S, orO; R⁸ is hydrogen or alkyl; Z is C═O, C═S, O═S═O, —NR⁸NR⁸—, or—C(═O)C(═O)—; A₁ and A₂ are, independently, optionally substitutedarylene or optionally substituted heteroarylene, wherein A₁ and A₂ are,independently, optionally substituted with one or more polar (PL)group(s), one or more non-polar (NPL) group(s), or a combination of oneor more polar (PL) group(s) and one or more non-polar (NPL) group(s); R¹is hydrogen, a polar group (PL), or a non-polar group (NPL); R² is R¹;NPL is a nonpolar group—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R^(4′),wherein: R³, R^(3′), and R^(3″) are, independently, selected fromhydrogen, alkyl, and alkoxy; R⁴ and R^(4′) are, independently, selectedfrom hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, andheteroaryl, any of which is optionally substituted with one or morealkyl or halo groups; U^(NPL) is absent or selected from O, S, S(═O),S(═O)₂, NR³, —C(═O)—, —C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—,C(═N—N(R³)₂)—, —C(═NR³)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—,—R³⁰—, —R³S—, —S—C═N—, and —C(═O)—NR³—O—, wherein groups with twochemically nonequivalent termini can adopt both possible orientations;the —(CH₂)_(pNPL)— alkylene chain is optionally substituted with one ormore amino or hydroxy groups, or is unsaturated; pNPL is 0 to 8; q1NPLand q2NPL are, independently, 0, 1, or 2; PL is a polar group selectedfrom halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene,and —(NR⁵)_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5′))_(q2PL)—V, wherein: R⁵,R^(5′) and R^(5″) are, independently, selected from hydrogen, alkyl, andalkoxy; U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵,—C(═O)—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—,—C(═NR⁵)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—,—S—C═N—, and —C(═O)—NR⁵—O—, wherein groups with two chemicallynonequivalent termini can adopt both possible orientations; V isselected from nitro, cyano, amino, hydroxy, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 4,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, guanyl, semicarbazone,aryl, heterocycle, and heteroaryl, any of which is optionallysubstituted with one or more of amino, halo, cyano, nitro, hydroxy,—NH(CH₂)_(p)NH₂ wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, amidino, guanidino,guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, orbenzyloxycarbonyl; the —(CH₂)_(pPL)— alkylene chain is optionallysubstituted with one or more amino or hydroxy groups, or is unsaturated;pPL is 0 to 8; and q1PL and q2PL are, independently, 0, 1, or 2.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XXIII:

R¹-[-A₁-W-A₂-W-]_(m)—R²  XXIII

or a pharmaceutically acceptable salt thereof,wherein:

A₁ and A₂ are, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein:

(i) A₁ and A₂ are, independently, optionally substituted with one ormore polar (PL) group(s), one or more non-polar (NPL) group(s), or acombination of one or more polar (PL) group(s) and one or more non-polar(NPL) group(s); or

(ii) one of A₁ or A₂ is as defined above and is optionally substitutedwith one or more polar (PL) group(s), one or more non-polar (NPL)group(s), or a combination of one or more polar (PL) group(s) and one ormore non-polar (NPL) group(s); and the other of A₁ or A₂ is the group—C≡C(CH₂)_(p)C≡C—, wherein p is 0 to 8, and the —(CH₂)_(p)— alkylenechain is optionally substituted with one or more amino or hydroxylgroups;

W is absent, or represents —CH₂—, —CH₂—CH₂—, —CH═CH—, or —C≡C—;

R¹ is

-   -   (i) hydrogen, a polar group (PL), or a non-polar group (NPL),        and R² is -A₁-R¹, wherein A₁ is as defined above and is        optionally substituted with one or more polar (PL) group(s), one        or more non-polar (NPL) group(s), or a combination of one or        more polar (PL) group(s) and one or more non-polar (NPL)        group(s); or    -   (ii) hydrogen, a polar group (PL), or a non-polar group (NPL),        and R² is -A₁-W-A₂-R¹, wherein each of A₁ and A₂ is as defined        above and is optionally substituted with one or more polar (PL)        group(s), one or more non-polar (NPL) group(s), or a combination        of one or more polar (PL) group(s) and one or more non-polar        (NPL) group(s); or    -   (iii) A′-W— and R² is -A₁-W-A′, wherein A′ is aryl or        heteroaryl, either of which is optionally substituted with one        or more polar (PL) group(s), one or more non-polar (NPL)        group(s), or a combination of one or more polar (PL) group(s)        and one or more non-polar (NPL) group(s); or    -   (iv) A′-W— and R² is -A′, wherein A′ is aryl or heteroaryl,        either of which is optionally substituted with one or more polar        (PL) group(s), one or more non-polar (NPL) groups(s), or a        combination of one or more polar (PL) group(s) and one or more        non-polar (NPL) group(s); or    -   (iv) R¹ and R² together form a single bond;

NPL is a nonpolar group independently selected from —B(OR⁴)₂ or—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R⁴, wherein:

R³, R^(3′), and R^(3″) are, independently, selected from hydrogen,alkyl, and alkoxy;

R⁴ is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,and heteroaryl, any of which is optionally substituted with one or morealkyl or halo groups;

U^(NPL) is absent or selected from O, S, S(═O), S(═O)₂, NR³, —(C═O)—,—(C═O)—N═N—NR³—, —(C═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³⁰—, —R³S—, —S—C═N— and—(C═O)—NR³—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

the —(CH₂)_(pNPL)— alkylene chain is optionally substituted with one ormore alkyl, amino or hydroxyl groups, or the alkylene chain isunsaturated;

pNPL is 0 to 8;

q1NPL and q2NPL are, independently, 0 to 2;

PL is a polar group selected from halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, and—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR⁵)_(q2PL)—V, wherein:

R⁵, R^(5′), and R^(5″) are, independently, selected from hydrogen,alkyl, and alkoxy;

U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵, —(C═O)—,—(C═O)—N═N—NR⁵—, —(C═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵O—, —R⁵S—, —S—C═N—, and—(C═O)—NR⁵—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

V is selected from nitro, cyano, amino, hydroxyl, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂, —N(CH₂CH₂NH₂)₂, diazamino,amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle, andheteroaryl, any of which is optionally substituted with one or more ofamino, halo, cyano, nitro, hydroxyl, —NH(CH₂)_(p)NH₂, —N(CH₂CH₂NH₂)₂,amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio,lower acylamino, or benzyloxycarbonyl;

the —(CH₂)_(pPL)— alkylene chain is optionally substituted with one ormore amino or hydroxyl groups, or the alkylene chain is unsaturated;

pPL is 0 to 8;

q1PL and q2PL are, independently, 0 to 2; and

m is 1 to about 25.

In some embodiments, the compound of Formula XXIII is of Formula XXIIIa:

R¹-A₁-W-A₂-W-A₁-R²  XXIIIa

wherein:

A₁ and A₂ are, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein:

-   -   (i) A₁ and A₂ are, independently, optionally substituted with        one or more polar (PL) group(s), one or more non-polar (NPL)        group(s), or a combination of one or more polar (PL) group(s)        and one or more non-polar (NPL) group(s); or    -   (ii) one of A₁ or A₂ is as defined above and is optionally        substituted with one or more polar (PL) group(s), one or more        non-polar (NPL) group(s), or a combination of one or more polar        (PL) group(s) and one or more non-polar (NPL) group(s); and the        other of A₁ or A₂ is the group —C≡C(CH₂)_(p)C≡C—, wherein p is 0        to 8, and the —(CH₂)_(p)— alkylene chain is optionally        substituted with one or more amino or hydroxyl groups;

W is —C≡C—;

R¹ is hydrogen, a polar group (PL), a non-polar group (NPL), or —W-A′,wherein A′ is aryl or heteroaryl, either of which is optionallysubstituted with one or more polar (PL) group(s), one or more non-polar(NPL) group(s), or a combination of one or more polar (PL) group(s) andone or more non-polar (NPL) group(s);

R² is R¹;

NPL is a nonpolar group—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R⁴;

R³, R^(3′), and R^(3″) are, independently, selected from hydrogen,alkyl, and alkoxy;

R⁴ is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,and heteroaryl, any of which is optionally substituted with one or morealkyl or halo groups;

U^(NPL) is absent or selected from O, S, S(═O), S(═O)₂, NR³, —(C═O)—,—(C═O)—N═N—NR³—, —(C═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³—O—, —R³—S—, —S—C═N—, and—(C═O)—NR³—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

the alkylene chain —(CH₂)_(pNPL)— is optionally substituted with one ormore alkyl, amino or hydroxyl groups, or the alkylene chain isunsaturated;

pNPL is 0 to 8;

q1NPL and q2NPL are, independently, 0 to 2;

PL is a polar group selected from halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, and—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5′))_(qPL)—V, wherein:

R⁵, R^(5′), and R^(5″) are, independently, selected from hydrogen,alkyl, and alkoxy;

U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵, —(C═O)—,—(C═O)—N═N—NR⁵—, —(C═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—, —S—C═N—, and—(C═O)—NR⁵—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

V is selected from nitro, cyano, amino, hydroxyl, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂, —N(CH₂CH₂NH₂)₂, diazamino,amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle, andheteroaryl, any of which is optionally substituted with one or more ofamino, halo, cyano, nitro, hydroxyl, —NH(CH₂)_(p)NH₂, —N(CH₂CH₂NH₂)₂,amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio,lower acylamino, or benzyloxycarbonyl;

the alkylene chain —(CH₂)_(pPL)— is optionally substituted with one ormore amino or hydroxyl groups, or the alkylene chain is unsaturated;

pPL is 0 to 8; and

q1PL and q2PL are, independently, 0 to 2.

In some embodiments, A₁ and A₂ are, independently, optionallysubstituted m-phenylene, wherein A₁ is optionally substituted with twopolar (PL) groups, and A₂ is unsubstituted; R¹ is a polar group; PL isindependently halo or—(NR⁵)_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5′))_(q2PL)—V, wherein: U^(PL) isabsent or selected from O, S, NR⁵, and —C(═O)—; V is selected fromamino, amidino, and guanidino, any of which is optionally substitutedwith one or more of amino, halo, —NH(CH₂)_(p)NH₂ wherein p is 1 to 4,—N(CH₂CH₂NH₂)₂, amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy,aminoalkythio, and lower acylamino; pPL is 0 to 8; and q1PL and q2PL are0.

In some embodiments, R¹ is halo; PL is or —U^(PL)—(CH₂)_(pPL)—V,wherein: U^(PL) is absent; V is selected from amino, amidino, andguanidino, any of which is optionally substituted with one or more ofamino and halo; and pPL is 0 to 6.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound chosenfrom:

or a pharmaceutically acceptable salt thereof.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XXIV:

R¹—X-A₁-X—Y-A₂-Y—X-A₁-X—R²  XXIV

or a pharmaceutically acceptable salt thereof,wherein:

X is NR⁸, O, S, or —N(R⁸)N(R⁸)—;

Y is C═O, C═S, or O═S=0;

R⁸ is hydrogen or alkyl;

A₁ and A₂ are, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein A₁ and A₂ are,independently, optionally substituted with one or more polar (PL)group(s), one or more non-polar (NPL) group(s), or a combination of oneor more polar (PL) group(s) and one or more non-polar (NPL) group(s);

R¹ is a polar group (PL) or a non-polar group (NPL);

R² is R¹;

NPL is a nonpolar group independently selected from —B(OR⁴)₂ and—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R^(4′),wherein:

R³, R^(3′), and R^(3″) independently, selected from hydrogen, alkyl, andalkoxy;

R⁴ and R^(4′) are, independently, selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, anyof which is optionally substituted with one or more alkyl or halogroups;

U^(NPL) is absent or selected from O, S, S(═O), S(═O)₂, NR³, —C(═O)—,—C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³O—, —R³S—, —S—C═N—, and—C(═O)—NR³—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

the —(CH₂)_(pNPL)— alkylene chain is optionally substituted with one ormore amino or hydroxy groups, or is unsaturated;

pNPL is 0 to 8;

q1NPL and q2NPL are, independently, 0, 1, or 2;

PL is a polar group selected from halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, and—(NR⁵)_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5′))_(q2PL)—V,

wherein:

R⁵, R^(5′), and R^(5″) are, independently, selected from hydrogen,alkyl, and alkoxy;

U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵, —C(═O)—,—C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—, —S—C═N—, and—C(═O)—NR⁵—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations;

V is selected from nitro, cyano, amino, hydroxy, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 4,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, guanyl, semicarbazone,aryl, heterocycle and heteroaryl, any of which is optionally substitutedwith one or more of amino, halo, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, amidino, guanidino, guanyl,aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, orbenzyloxycarbonyl;

the —(CH₂)_(pPL)— alkylene chain is optionally substituted with one ormore amino or hydroxy groups, or is unsaturated;

pPL is 0 to 8; and

q1PL and q2PL are, independently, 0, 1, or 2.

In some embodiments, A₁ is m-phenylene substituted with one (PL) groupand one non-polar (NPL) group; A₂ is unsubstituted m-pyrimidinylene orm-pyrimidinylene substituted with one or two polar (PL) group(s); NPL isR^(4′), wherein R^(4′) is (C₁-C₆)alkyl optionally substituted with oneor more halo groups; PL is —U^(PL)—(CH₂)_(pPL)—V, wherein: U^(PL) is Oor S; V is selected from amino, amidino, and guanidino; and pPL is 0 to6.

In some embodiments, A₁ is m-phenylene substituted with one (PL) groupand one non-polar (NPL) group; A₂ is unsubstituted m-phenylene orm-phenylene substituted with one or two polar (PL) group(s); NPL is R⁴,wherein R⁴ is (C₁-C₆)alkyl optionally substituted with one or more halogroups; PL is —U^(PL)(CH₂)_(pPL)—V, wherein: U^(PL) is O or S; V isselected from amino, amidino, and guanidino; and pPL is 0 to 6.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound chosenfrom:

or a pharmaceutically acceptable salt thereof.

The present invention discloses compositions comprising any of thecompounds described herein or any combination thereof. Polymers aregenerally defined as synthetic compounds assembled from monomer subunitsthat are polydisperse in molecular weight, and are most commonlyprepared by one-pot synthetic procedures. The term “polymer” as usedherein refers to a macromolecule comprising a plurality of repeatingunits or monomers. The term includes homopolymers, which are formed froma single type of monomer, and copolymers, which are formed from two ormore different monomers. In copolymers, the monomers may be distributedrandomly (random copolymer), in alternating fashion (alternatingcopolymers), or in blocks (block copolymer). The polymers of the presentinvention are either homopolymers or alternating copolymers having about2 monomer units to about 500 monomer units, with average molecularweights that range from about 300 Daltons to about 1,000,000 Daltons, orfrom about 400 Daltons to about 120,000 Daltons. Preferred polymers arethose having about 5 to about 100 monomer units, with average molecularweights that range from about 1,000 Daltons to about 25,000 Daltons.

The term “oligomer” as used herein refers to a homogenous polymer with adefined sequence and molecular weight. Modern methods of solid phaseorganic chemistry have allowed the synthesis of homodisperse,sequence-specific oligomers with molecular weights approaching 5,000Daltons. An oligomer, in contrast to a polymer, has a defined sequenceand molecular weight and is usually synthesized either by solid phasetechniques or by step-wise solution chemistry and purified tohomogeneity. Oligomers of the present invention are those having about 2monomer units to about 25 monomer units, with molecular weights thatrange from about 300 Daltons to about 6,000 Daltons. Suitable oligomersare those having about 2 monomer units to about 10 monomer units, withmolecular weights that range from about 300 Daltons to about 2,500Daltons.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound ofFormula XXV:

A-(B)_(n1)-(D)_(m1)-H  XXV

or a pharmaceutically acceptable salt thereof,wherein:

A is the residue of a chain transfer agent;

B is —[CH₂—C(R¹¹)(B₁₁)]—, wherein B₁₁ is —X₁₁—Y₁₁—Z₁₁, wherein

X₁₁ is carbonyl (—C(═O)—) or optionally substituted C₁₋₆ alkylene; orX₁₁ is absent;

Y₁₁ is O, NH, or optionally substituted C₁₋₆ alkylene; or Y₁₁ is absent;

Z₁₁ is —Z_(11A)—Z_(11B), wherein Z_(11A) is alkylene, arylene, orheteroarylene, any of which is optionally substituted; or Z_(11A) isabsent; and Z_(11B) is -guanidino, -amidino, —N(R³)(R⁴), or—N⁺(R³)(R⁴)(R⁵), wherein R³, R⁴, and R⁵ are, independently, hydrogen,alkyl, aminoalkyl, aryl, heteroaryl, heterocyclic, or aralkyl; or

Z₁₁ is pyridinium

or phosphonium

wherein R⁸¹, R⁹¹¹, R⁹²¹, and R⁹³¹ are, independently, hydrogen or alkyl;

R¹¹ is hydrogen or C₁₋₄ alkyl;

D is —[CH₂—C(R²¹)(D₂₁)]—, wherein D₂₁ is —X₂₁—Y₂₁—Z₂₁, wherein

X₂₁ is carbonyl (—C(═O)—) or optionally substituted C₁₋₆ alkylene; orX₂₁ is absent;

Y₂₁ is O, NH, or optionally substituted C₁₋₆ alkylene, or Y₂₁ is absent;

Z₂₁ is alkyl, cycloalkyl, alkoxy, aryl, or aralkyl, any of which isoptionally substituted;

R²¹ is hydrogen or C₁₋₄ alkyl;

m₁, the mole fraction of D, is about 0.1 to about 0.9; and

n₁, the mole fraction of B, is 1-m₁;

wherein the compound is a random copolymer of B and D, and

wherein the copolymer has a degree of polymerization of about 5 to about50.

In some embodiments, A is C₁₋₄ alkoxycarbonyl(C₁₋₄)alkylthio; X₁₁ andX₂₁ are carbonyl; Y₁₁ and Y₂₁ are 0; Z₁₁ is —Z_(11A)—Z_(11B), whereinZ_(11A) is C₁₋₆ alkylene optionally substituted with C₁₋₄ alkyl or aryl;and Z_(11B) is —N(R³¹)(R⁴¹) or —N⁺(R³¹)(R⁴¹)(R⁵¹), wherein R³¹, R⁴¹, andR⁵¹ are independently hydrogen C₁₋₄ alkyl; Z₂₁ is C₁₋₆ alkyl, C₁₋₆ aryl,or C₁₋₆ ar(C₁₋₄)alkyl; and R¹¹ and R²¹ are, independently, hydrogen ormethyl; m₁ is about 0.35 to about 0.60; and wherein the copolymer has adegree of polymerization of about 5 to about 10.

In some embodiments, the copolymer has a molecular weight from about2,000 Daltons to about 15,000 Daltons. In some embodiments, thecopolymer has a molecular weight from about 2,000 Daltons to about 3,000Daltons. In some embodiments, the copolymer has a molecular weight fromabout 3,000 Daltons to about 4,000 Daltons. In some embodiments, thecopolymer has a molecular weight from about 4000 Daltons to about 5,000Daltons. In some embodiments, the copolymer has a molecular weight fromabout 5000 Daltons to about 6,000 Daltons. In some embodiments, thecopolymer has a molecular weight from about 6,000 Daltons to about 7,000Daltons. In some embodiments, the copolymer has a molecular weight fromabout 7,000 Daltons to about 8,000 Daltons. In some embodiments, thecopolymer has a molecular weight from about 8,000 Daltons to about 9,000Daltons. In some embodiments, the copolymer has a molecular weight fromabout 9,000 Daltons to about 10,000 Daltons. In some embodiments, thecopolymer has a molecular weight from about 10,000 Daltons to about11,000 Daltons. In some embodiments, the copolymer has a molecularweight from about 11,000 Daltons to about 12,000 Daltons.

In some embodiments, the copolymer is a polymethcrylate. In someembodiments, one of B and D is amino-ethyl methacrylate the other of Band D is butyl-methacrylate, ethyl-methacrylate, or methyl-methacrylate.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound chosenfrom:

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound chosenfrom Table 1:

TABLE 1 Compd. No. Structure  1

 2

 3

 4

 5

 6 (Z)

 7

 8

 9

 10

 11

 12

 13

 14

 15

 16

 17

 18

 19

 20

 21

 22

 23

 24

 25

 26

 27

 28

 29

 30

 31

 32

 33

 34

 35

 36

 37

 38

 39

 40

 41

 42

 43

 44

 45

 46

 47

 48

 49

 50

 51

 52

 53

 54

 55

 56

 57

 58

 59

 60

 61

 62

 63

 64

 65

 66

 67

 68

 69

 70

 71

 72

 73

 74

 75

 76

 77

 78

 79

 80

 81

 82

 83

 84

 85

 86

 87

 88

 89

 90

 91

 92

 93

 94

 95

 96

 97

 98

 99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

The exemplary compounds (and/or their salts) in Table 1 were prepared bymethods such as those reported in U.S. Patent Application PublicationNos. U.S. 2005/0287108, U.S. 2006/0041023, U.S. Pat. No. 7,173,102, WO2005/123660, WO 2004/082643, WO 2006/093813, and U.S. patent applicationSer. No. 12/510,593 filed Jul. 28, 2009.

The present invention also provides methods of treating and/orpreventing mucositis in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount of a compound chosenfrom Table 2:

TABLE 2 Com- pound Num- ber Compound Structure 201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

The exemplary compounds (and/or their salts) in Table 2 were prepared bymethods such as those reported in U.S. Patent Application PublicationNos. U.S. 2005/0287108, U.S. 2006/0041023, U.S. Pat. No. 7,173,102, WO2005/123660, WO 2004/082643, WO 2006/093813, and U.S. patent applicationSer. No. 12/510,593 filed Jul. 28, 2009.

The compounds of the invention may be useful for treating and/orpreventing mucositis by administering to the patient an effective amountof a compound of the invention or a salt thereof, or a pharmaceuticalcomposition comprising a compound of the invention or a salt thereof.The compound or salt, or composition thereof, can be administeredsystemically or topically and can be administered to any body site ortissue.

In some embodiments, the present methods for treating and/or preventingmucositis can be used in a patient who receives chemotherapy and/orradiation therapy for cancer. In some embodiments, the patient isreceiving or will be receiving high-dose chemotherapy prior tohematopoietic cell transplantation. In some embodiments, the patient isreceiving or will be receiving radiation therapy for tumors of the headand neck. In some embodiments, the patient is receiving or will bereceiving induction therapy for leukemia. In some embodiments, thepatient is receiving or will be receiving conditioning regimens for bonemarrow transplant. In some embodiments, the patient is experiencing orwill be experiencing basal epithelial cell death.

In some embodiments of the invention, the compound used for treatingand/or preventing mucositis is not Compound Y. In some embodiments ofthe invention, the compound used for treating and/or preventingmucositis is not Compound Z. In some embodiments of the invention, thecompound used for treating and/or preventing mucositis is not Compound Yor Compound Z.

Although the disclosed compounds are suitable, other functional groupscan be incorporated into the compound with an expectation of similarresults. In particular, thioamides and thioesters are anticipated tohave very similar properties. The distance between aromatic rings canimpact the geometrical pattern of the compound and this distance can bealtered by incorporating aliphatic chains of varying length, which canbe optionally substituted or can comprise an amino acid, a dicarboxylicacid or a diamine. The distance between and the relative orientation ofmonomers within the compounds can also be altered by replacing the amidebond with a surrogate having additional atoms. Thus, replacing acarbonyl group with a dicarbonyl alters the distance between themonomers and the propensity of dicarbonyl unit to adopt an antiarrangement of the two carbonyl moiety and alter the periodicity of thecompound. Pyromellitic anhydride represents still another alternative tosimple amide linkages which can alter the conformation and physicalproperties of the compound. Modern methods of solid phase organicchemistry (E. Atherton and R. C. Sheppard, Solid Phase Peptide SynthesisA Practical Approach IRL Press Oxford 1989) now allow the synthesis ofhomodisperse compounds with molecular weights approaching 5,000 Daltons.Other substitution patterns are equally effective.

The compounds of the invention also include derivatives referred to asprodrugs. As used herein, the term “prodrug” refers to a derivative of aknown direct acting drug, which derivative has enhanced deliverycharacteristics and therapeutic value as compared to the drug, and istransformed into the active drug by an enzymatic or chemical process.

It is understood that the present invention encompasses the use, whereapplicable, of stereoisomers, diastereomers and optical stereoisomers ofthe compounds of the invention, as well as mixtures thereof.Additionally, it is understood that stereoisomers, diastereomers, andoptical stereoisomers of the compounds of the invention, and mixturesthereof, are within the scope of the invention. By way of non-limitingexample, the mixture may be a racemate or the mixture may compriseunequal proportions of one particular stereoisomer over the other.Additionally, the compounds of the invention can be provided as asubstantially pure stereoisomers, diastereomers and opticalstereoisomers (such as epimers).

The compounds of the invention can be provided in the form of anacceptable salt (i.e., a pharmaceutically acceptable salt). Salts can beprovided for pharmaceutical use, or as an intermediate in preparing thepharmaceutically desired form of the compounds of the invention. Oneexample of a salt that can be considered to be acceptable is thehydrochloride acid addition salt. Hydrochloride acid addition salts areoften acceptable salts when the pharmaceutically active agent has anamine group that can be protonated. Since the compounds of the inventionmay be polyionic, such as a polyamine, the acceptable salt can beprovided in the form of a poly(amine hydrochloride).

The compounds of the invention may be used in methods for treatingand/or preventing mucositis. For example, compounds of the invention maybe used therapeutically to treat and/or prevent mucositis in patientssuch as animals, including humans and non-human vertebrates such aswild, domestic and farm animals.

In some embodiments, suitable dosage ranges for intravenous (i.v.)administration are 0.01 mg to 500 mg per kg body weight, 0.1 mg to 100mg per kg body weight, 1 mg to 50 mg per kg body weight, or 10 mg to 35mg per kg body weight. Suitable dosage ranges for other modes ofadministration can be calculated based on the forgoing dosages as knownby those skilled in the art. For example, recommended dosages forintradermal, intramuscular, intraperitoneal, subcutaneous, epidural,sublingual, intracerebral, intravaginal, transdermal administration oradministration by inhalation are in the range of 0.001 mg to 200 mg perkg of body weight, 0.01 mg to 100 mg per kg of body weight, 0.1 mg to 50mg per kg of body weight, or 1 mg to 20 mg per kg of body weight.Effective doses may be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems. Such animal models andsystems are well known in the art.

Polyamides and polyesters that are useful for the present invention canbe prepared by typical condensation polymerization and additionpolymerization processes (see, for example, G. Odian, Principles ofPolymerization, John Wiley & Sons, Third Edition (1991), and M. Steven,Polymer Chemistry, Oxford University Press (1999)). Most commonly, thepolyamides are prepared by a) thermal dehydration of amine salts ofcarboxylic acids, b) reaction of acid chlorides with amines, and c)aminolysis of esters. Methods a) and c) are of limited use inpolymerizations of aniline derivatives which are generally preparedutilizing acid chlorides. The skilled chemist, however, will recognizethat there are many alternative active acylating agents, for examplephosphoryl anhydrides, active esters or azides, which may replace anacid chloride and which, depending of the particular polymer beingprepared, may be superior to an acid chloride. The acid chloride routeis probably the most versatile and has been used extensively for thesynthesis of aromatic polyamides.

Homopolymers derived from substituted aminobenzoic acid derivatives canalso prepared in a stepwise fashion. A stepwise process comprisescoupling an N-protected amino acid to an amine (or hydroxy group) andsubsequently removing the amine-protecting group and repeating theprocess. These techniques have been highly refined for synthesis ofspecific peptides, allow for the synthesis of specific sequences, andboth solid-phase and solution techniques for peptide synthesis aredirectly applicable to the present invention. An alternative embodimentof the present invention is the corresponding polysulfonamides that canbe prepared in analogous fashion by substituting sulfonyl chlorides forcarboxylic acid chlorides.

The most common method for the preparation of polyureas is the reactionof diamines with diisocyanates (see, Yamaguchi et al., Polym. Bull.,2000, 44, 247). This exothermic reaction can be carried out by solutiontechniques or by interfacial techniques. One skilled in organic andpolymer chemistry will appreciate that the diisocyanate can be replacedwith a variety of other bis-acylating agents, such as phosgene orN,N′-(diimidazolyl)carbonyl, with similar results. Polyurethanes areprepared by comparable techniques using a diisocyanate and a dialcoholor by reaction of a diamine with a bis-chloroformate.

The syntheses of compounds of the invention can be carried out byroutine and/or known methods such as those disclosed in, for example,U.S. Patent Application Publication Nos. 2005-0287108, 2006-0041023,U.S. Pat. No. 7,173,102, International Publication Nos. WO 2005/123660,WO 2004/082643, and WO 2006/093813, and U.S. Application Publication No.2010-0081665, each of which is incorporated herein by reference in itsentirety. Numerous pathways are available to incorporate polar andnonpolar side chains. Phenolic groups on the monomer can be alkylated.Alkylation of the commercially available phenol will be accomplishedwith standard Williamson ether synthesis for the non-polar side chainwith ethyl bromide as the alkylating agent. Polar sidechains can beintroduced with bifunctional alkylating agents such as BOC—NH(CH₂)₂Br.Alternately, the phenol group can be alkylated to install the desiredpolar side chain function by employing the Mitsonobu reaction withBOC—NH(CH₂)₂—OH, triphenyl phosphine, and diethylacetylenedicarboxylate. Standard conditions for reduction of the nitrogroups and hydrolysis of the ester afford the amino acid. With theaniline and benzoic acid in hand, coupling can be effected under avariety of conditions. Alternatively, the hydroxy group of the(di)nitrophenol can be converted to a leaving group and a functionalityintroduced under nucleophilic aromatic substitution conditions. Otherpotential scaffolds that can be prepared with similar sequences aremethyl 2-nitro-4-hydroxybenzoate and methyl 2-hydroxy-4-nitrobenzoate.

The compounds of the invention can also be designed using computer-aidedcomputational techniques, such as de novo design techniques, to embodythe amphiphilic properties. In general, de novo design of compounds isperformed by defining a three-dimensional framework of the backboneassembled from a repeating sequence of monomers using molecular dynamicsand quantum force field calculations. Next, side groups arecomputationally grafted onto the backbone to maximize diversity andmaintain drug-like properties. The best combinations of functionalgroups are then computationally selected to produce a cationic,amphiphilic structures. Representative compounds can be synthesized fromthis selected library to verify structures and test their biologicalactivity. Novel molecular dynamic and coarse grain modeling programshave also been developed for this approach because existing force fieldsdeveloped for biological molecules, such as peptides, were unreliable inthese oligomer applications (see, Car et al., Phys. Rev. Lett., 1985,55, 2471-2474; Siepmann et al., Mol. Phys., 1992, 75, 59-70; Martin etal., J. Phys. Chem., 1999, 103, 4508-4517; and Brooks et al., J. Comp.Chem., 1983, 4, 187-217). Several chemical structural series ofcompounds have been prepared. See, for example, InternationalPublication No. WO 2002/100295, which is incorporated herein byreference in its entirety. The compounds of the invention can beprepared in a similar manner. Molecular dynamic and coarse grainmodeling programs can be used for a design approach. See, for example,U.S. Application Publication No. 2004-0107056, and U.S. ApplicationPublication No. 2004-0102941, each of which is incorporated herein byreference in its entirety.

An example of the design, synthesis, and testing of arylamide polymersand oligomers, a related group of compounds of the invention, ispresented in Tew et al., Proc. Natl. Acad. Sci. USA, 2002, 99,5110-5114, which is incorporated herein by reference in its entirety.

Compounds of the invention can be synthesized by solid-phase syntheticprocedures well know to those of skill in the art (see, Tew et al.,Proc. Natl. Acad. Sci. USA, 2002, 99, 5110-5114; Barany et al., Int. J.Pept. Prot. Res., 1987, 30, 705-739; Solid-phase Synthesis: A PracticalGuide, Kates, S. A., and Albericio, F., eds., Marcel Dekker, New York(2000); and Dorwald, F. Z., Organic Synthesis on Solid Phase: Supports,Linkers, Reactions, 2nd Ed., Wiley-VCH, Weinheim (2002)).

The compounds of the invention can be administered in any conventionalmanner by any route where they are active. Administration can besystemic, topical, or oral. For example, administration can be, but isnot limited to, parenteral, subcutaneous, intravenous, intramuscular,intraperitoneal, transdermal, oral, buccal, or ocular routes, orintravaginally, by inhalation, by depot injections, or by implants.Thus, modes of administration for the compounds of the invention (eitheralone or in combination with other pharmaceuticals) can be, but are notlimited to, sublingual, injectable (including short-acting, depot,implant and pellet forms injected subcutaneously or intramuscularly), orby use of vaginal creams, suppositories, pessaries, vaginal rings,rectal suppositories, intrauterine devices, and transdermal forms suchas patches and creams. The selection of the specific route ofadministration and the dose regimen is to be adjusted or titrated by theclinician according to methods known to the clinician to obtain thedesired clinical response. The amount of compounds of the invention tobe administered is that amount which is therapeutically effective. Thedosage to be administered will depend on the characteristics of thesubject being treated, e.g., the particular animal treated, age, weight,health, types of concurrent treatment, if any, and frequency oftreatments, and can be easily determined by one of skill in the art(e.g., by the clinician). The amount of a compound described herein thatwill be effective in the treatment and/or prevention of mucositis willdepend on the nature of the mucositis, and can be determined by standardclinical techniques. In addition, in vitro or in vivo assays mayoptionally be employed to help identify optimal dosage ranges. Theprecise dose to be employed in the compositions will also depend on theroute of administration, and the seriousness of the disorder, and shouldbe decided according to the judgment of the practitioner and eachpatient's circumstances. However, a suitable dosage range for oraladministration is, generally, from about 0.001 milligram to about 200milligrams per kilogram body weight. In some embodiments, the oral doseis from about 0.01 milligram to 100 milligrams per kilogram body weight,from about 0.01 milligram to about 70 milligrams per kilogram bodyweight, from about 0.1 milligram to about 50 milligrams per kilogrambody weight, from 0.5 milligram to about 20 milligrams per kilogram bodyweight, or from about 1 milligram to about 10 milligrams per kilogrambody weight. In some embodiments, the oral dose is about 5 milligramsper kilogram body weight.

The pharmaceutical compositions and/or formulations containing thecompounds of the invention and a suitable carrier can be solid dosageforms which include, but are not limited to, tablets, capsules, cachets,pellets, pills, powders and granules; topical dosage forms whichinclude, but are not limited to, solutions, powders, fluid emulsions,fluid suspensions, semi-solids, ointments, pastes, creams, gels andjellies, and foams; and parenteral dosage forms which include, but arenot limited to, solutions, suspensions, emulsions, and dry powder;comprising an effective amount of a compound of the invention. It isalso known in the art that the active ingredients can be contained insuch formulations with pharmaceutically acceptable diluents, fillers,disintegrants, binders, lubricants, surfactants, hydrophobic vehicles,water soluble vehicles, emulsifiers, buffers, humectants, moisturizers,solubilizers, preservatives and the like. The means and methods foradministration are known in the art and an artisan can refer to variouspharmacologic references for guidance (see, for example, ModernPharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman& Gilman's The Pharmaceutical Basis of Therapeutics, 6th Edition,MacMillan Publishing Co., New York (1980)).

In some embodiments, the compounds described herein can be used withagents including, but not limited to, topical analgesics (e.g.,lidocaine), barrier devices (e.g., GelClair), or rinses (e.g.,Caphosol).

The compounds of the invention can be formulated for parenteraladministration by injection, such as by bolus injection or continuousinfusion. The compounds of the invention can be administered bycontinuous infusion subcutaneously over a period of about 15 minutes toabout 24 hours. Formulations for injection can be presented in unitdosage form, such as in ampoules or in multi-dose containers, with anadded preservative. The compositions can take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and can containformulatory agents such as suspending, stabilizing and/or dispersingagents.

For oral administration, the compounds of the invention can beformulated readily by combining these compounds with pharmaceuticallyacceptable carriers well known in the art. Such carriers enable thecompounds of the invention to be formulated as tablets, pills, dragees,capsules, liquids, gels, syrups, slurries, suspensions and the like, fororal ingestion by a patient to be treated. Pharmaceutical preparationsfor oral use can be obtained by, for example, adding a solid excipient,optionally grinding the resulting mixture, and processing the mixture ofgranules, after adding suitable auxiliaries, if desired, to obtaintablets or dragee cores. Suitable excipients include, but are notlimited to, fillers such as sugars, including, but not limited to,lactose, sucrose, mannitol, and sorbitol; cellulose preparations suchas, but not limited to, maize starch, wheat starch, rice starch, potatostarch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, andpolyvinylpyrrolidone (PVP). If desired, disintegrating agents can beadded, such as, but not limited to, the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate.

Dragee cores can be provided with suitable coatings. For this purpose,concentrated sugar solutions can be used, which can optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments can be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations which can be used orally include, but arenot limited to, push-fit capsules made of gelatin, as well as soft,sealed capsules made of gelatin and a plasticizer, such as glycerol orsorbitol. The push-fit capsules can contain the active ingredients inadmixture with filler such as lactose, binders such as starches, and/orlubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds can be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers can be added. Allformulations for oral administration should be in dosages suitable forsuch administration.

For buccal administration, the compositions can take the form of, suchas, tablets or lozenges formulated in a conventional manner

For administration by inhalation, the compounds of the invention for useaccording to the present invention are conveniently delivered in theform of an aerosol spray presentation from pressurized packs or anebulizer, with the use of a suitable propellant, such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit can be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, such as gelatin for use in an inhaler or insufflator can beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch.

The compounds of the invention can also be formulated in rectalcompositions such as suppositories or retention enemas, such ascontaining conventional suppository bases such as cocoa butter or otherglycerides.

In addition to the formulations described previously, the compounds ofthe invention can also be formulated as a depot preparation. Such longacting formulations can be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Depotinjections can be administered at about 1 to about 6 months or longerintervals. Thus, for example, the compounds can be formulated withsuitable polymeric or hydrophobic materials (for example as an emulsionin an acceptable oil) or ion exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

In transdermal administration, the compounds of the invention, forexample, can be applied to a plaster, or can be applied by transdermal,therapeutic systems that are consequently supplied to the organism.

The pharmaceutical compositions of the compounds of the invention alsocan comprise suitable solid or gel phase carriers or excipients.Examples of such carriers or excipients include, but are not limited to,calcium carbonate, calcium phosphate, various sugars, starches,cellulose derivatives, gelatin, and polymers such as polyethyleneglycols.

The present invention also provides compounds of the invention, orcompositions comprising the same, for use in treating and/or preventingmucositis in a patient. The present invention also provides compounds ofthe invention, or compositions comprising the same, for use in treatingand/or preventing mucositis. The present invention also providescompounds of the invention, or compositions comprising the same, for usein preparation of a medicament for treating and/or preventing mucositisin a patient.

The compounds of the invention can also be administered in combinationwith other active ingredients such as, for example, palifermin and/orNX002, or other known compounds useful for treating and/or preventingmucositis.

The present invention also provides methods for treating and/orpreventing mucositis in an animal comprising administering to the animalin need thereof an effective amount of a compound of the invention. Thepresent invention also provides methods for treating and/or preventingmucositis in an animal comprising administering to the animal in needthereof a composition of the invention. The present invention alsoprovides methods for treating and/or preventing mucositis comprisingadministering to the animal an effective amount of a compound or salt ofthe invention.

The present invention also provides compounds of the invention, orcompositions comprising the same, for use in treating and/or preventingmucositis in a patient. The present invention also provides compounds ofthe invention, or compositions comprising the same, for use inpreparation of a medicament for treating and/or preventing mucositis ina patient.

The structures depicted herein may omit necessary hydrogen atoms tocomplete the appropriate valency. Thus, in some instances a carbon atomor nitrogen atom may appear to have an open valency (i.e., a carbon atomwith only two bonds showing would implicitly also be bonded to twohydrogen atoms; in addition, a nitrogen atom with a single bond depictedwould implicitly also be bonded to two hydrogen atoms). For example,“—N” would be considered by one skilled in the art to be “—NH₂.” Thus,in any structure depicted herein wherein a valency is open, one or morehydrogen atoms, as appropriate, is implicit, and is only omitted forbrevity.

In order that the invention disclosed herein may be more efficientlyunderstood, examples are provided below. It should be understood thatthese examples are for illustrative purposes only and are not to beconstrued as limiting the invention in any manner.

Throughout these examples, molecular cloning reactions, and otherstandard recombinant DNA techniques, were carried out according tomethods described in Maniatis et al., Molecular Cloning—A LaboratoryManual, 2nd ed., Cold Spring Harbor Press (1989), using commerciallyavailable reagents, except where otherwise noted.

EXAMPLES Example 1 Synthesis Synthesis of Compound 1

Step 1: The diacid and dianiline (2 equiv.) were mixed in pyridine, andEDCI was added. The reaction mixture was stirred at room temperature for24 hours before the solvent was removed. The resulting solid was washedwith water and recrystallized in DCM/Hexane.

Step 2: Product from step 1 and 5-bisBocguanidino pentoic acid weremixed and dissolved in pyridine. The solution was cooled to 0° C. beforePOCl₃ was added to the mixture. The reaction mixture was stirred at 0°C. for 2 hours before it is quenched with ice water. The product waspurified by column chromatography.

Step 3: Product from step 2 was treated with HCl in ethyl acetate for 6hours. The product was collected by filtration. The purification wasdone by reverse phase column chromatography.

Compound 6, 87 and 88 are made by similar procedure using differentdiacid in the first step.

Compound Diacids  6

87

88

Synthesis of Compound 4

Step 1: A solution of acid (3.18 g) and concentrated H₂SO₄ (˜4 mL) inmethanol (64 mL) was heated under reflux for 2 days. The product wasobtained upon cooling and was filtered off and washed with a smallamount of MeOH to give pure methyl ester.

Step 2: A flame dried 100 mL round bottom flask was charged with diol 2(1.32 g, 5.84 mmol), 5-N-tert-butoxycarbonylamino-1-pentanol (2.37 g,11.7 mmol), Ph₃P (3.06 g, 11.7 mmol), and THF (15 mL). The resultingsolution was cooled to 0° C. under Argon, and DEAD (2.16 mL) was addedto the solution dropwise to give a dard red solution. The mixture wasthen warmed to room temperature and stirred until no starting materialremained (ca. 10 h). THF was removed and the residue was purified bycolumn chromatography (DCM/hexane/ether=4:4:1) to give pure product.

Step 3: To the solution of diester (3.11 mmol) in methanol (10 mL),there was added 2 N LiOH (5.1 mL) slowly. The resulting solution wasstirred at room temperature overnight, the solvent was then removed invacuo. The residue was redissolved in water (150 mL), and the aqueoussolution was acidified to pH=2 using 6 N HCl. Pure product was obtainedby filtration.

Step 4: The diacid, N,N-dimethylethane-1,2-diamine (2 equiv.), HOAT (2equiv.), HATU (2 equiv.) and DIEA (5 equiv.) were mixed in DMF andstirred at room temperature overnight. The solution was diluted withwater, and the product was purified by reverse phase chromatography.

Step 5: Product from step 4 was treated with 50% TFA in DCM for 3 hours.The solution was concentrated to an oil and triturated with cold ether.The product was collected by filtration and dried under vacuum.

Synthesis of Compound 2

Step 1: One 1 L round bottom flask was fitted with a magnetic stirrercondenser, drying tube and a heating mantel. Diacid (20 g) was added andslurried in toluene (256 mL). DMF (1 mL) was added, followed by SOCl₂(64 mL). The resulting slurry was heated at reflux and complete solutionwas obtained after 10 minutes. The reaction mixture was cooled to roomtemperature after 90 minutes of reflux and stirred overnight. Theproduct crystallized out from the solution. The mixture was cooled at 5°C. for one hour. The solid was collected by filtration and washed withcold toluene. Yield: 19.71 g.

Step 2: The mono Boc protected amine was dissolved in DCM and DIEA wasadded. Acid chloride was added to the solution and the reaction mixturewas stirred at room temperature for 2 hours and the product precipitatedout. The product was collected by filtration.

Step 3: The diacid, N,N-dimethylethane-1,2-diamine (1 equiv.), HOAT (1equiv.), HATU (1 equiv.) and DIEA (2 equiv.) were mixed in DMF andstirred at room temperature overnight. The solution was diluted withwater, and the product was purified by reverse phase chromatography.

Step 4: Diamine, acid (2.2 equiv.), HOAT (2.2 equiv.), HATU (2.2 equiv.)and DIEA (5 equiv.) were dissolved in DMF and stirred at roomtemperature overnight. The mixture was added water and extracted withDCM. The organic layer was concentrated to generate the crude solid. Theproduct was purified by reverse phase chromatography.

Step 5: Product from step 4 was treated with 50% TFA in DCM for 3 hours.The solution was concentrated to an oil and triturated with cold ether.The product was collected by filtration and dried under vacuum.

Synthesis of Compound 3

Compound 3 was made by similar procedure as compound 2 except one extrastep.

The Boc of the precursor was removed by treatment of 50% TFA/DCM. Afterthe solid was washed and dried under vacuum, it was dissolved inacetonitrile and water, DIEA (15 equiv.) was added and followed bydi-Boc pyrazole. The reaction mixture was stirred at room temperatureovernight. The solvent was removed and the solid was redissolved in DCM.After trituration with hexane/diethyl ether, the product was collectedby filtration and dried under vacuum.

Synthesis of compound 103, 104, 105 and 106 were synthesized usingsimilar method as compound 3.

Synthesis of Compound 5

The damine, monoacid (2. equiv.), HATU (2. equiv.) and HOAT (2. equiv.)were mixed and dissolved in DMF. DIEA (4 equiv.) was added to the DMFsolution and the reaction mixture was stirred at room temperatureovernight. The solution was diluted with water and extracted with DCM.The organic layer was washed with water before the solvent was removed.

The solid was treated with 50% TFA in DCM for 3 hours before thesolution was concentrated. The product was precipitated with diethylether and purified by reverse phase chromatography.

Synthesis of Compound 86

Step 1: The diacid was suspended in chloroform and ethyl chloroformate(2.2 equiv.) was added. DIEA (2.2 equiv.) was added to the mixture andstirred for 2 hours before monoBoc hexyldiamine (2.2 equiv.) was added.The reaction mixture was stirred for 4 hours before it was addedN,N-dimethyl ethylenediamine (1.5 equiv.). The reaction mixture wasstirred overnight. The solution was diluted with DCM and washed withwater. After the solvent was removed, the product was purified byreverse phase column chromatography.

Step 2: Product from step 3 was treated with 50% TFA in DCM for 2 hoursbefore the solvent was removed. The solid was dried under vacuum at 35°C. for 2 hours before it was dissolved in DMF. HATU, HOAT and monoacidwas added to the solution. Then DIEA was added. The mixture was stirredovernight at room temperature. After diluted with water, the product wasextracted with DCM. The organic layer was washed with water,concentrated to solid and dried under vacuum overnight. The solid wastreated with 50% TFA/DCM for 2 hours. The final product was purified byreverse phase column chromatography.

Synthesis of Compound 89

A mixture of 47.75 g (100.0 mmol) of 1 and 18.12 g (100.0 mmol) of 2 in500 mL of anhydrous CHCl₃ was stirred at room temperature under Ar and,after 30 minutes, a clear orange solution was observed. The reaction wasmonitored by tlc and found to be complete after 60 hours. The reactionwas concentrated in vacuo to a brown syrup that was dissolved betweenEtOAc and water. The layers were separated and the aqueous layer wasextracted twice more with EtOAc. The EtOAc fractions were combined andwashed four times with water (followed removal of byproduct HOSu bytlc). The EtOAc layer was then washed once with 10% citric acid(aqueous), twice with water, three times (carefully) with saturatedNaHCO₃, and once with brine. The EtOAc layer was dried over Na₂SO₄,filtered, and concentrated to afford 53.48 g (98%) of 3.

A solution of 26.74 g (49.19 mmol) of 3 in a mixture of 294 mL of THFand 196 mL of MeOH was treated with 98 mL of 2.0 M LiOH (aqueous) (196mmol) and the resultant mixture was stirred at room temperature for 18hours. The reaction mixture was cooled in an ice bath then treated with196 mL of cold 1.0 M HCl (aqueous) to neutralize. The quenched reactionwas partially concentrated in vacuo to an aqueous slurry that wasextracted with EtOAc until tlc showed the extraction was complete. TheEtOAc layer was dried over Na₂SO₄, filtered, and concentrated to afford25.71 g (99%) of 4 as a beige solid.

3 (26.74 g, 49.19 mmol) was introduced to a 1 L round bottom flask thatwas equipped with a ground glass stopper (secured by a Keck clamp) andtreated with 385 mL of a cold 10% solution (v/v) of TFA in CH₂Cl₂ (500mmol of TFA). The resultant brick red solution was allowed to warm toroom temperature. The reaction was followed by tlc and all of 3 wasconsumed after 24 hours. The reaction was diluted with twice its volumeof CH₃CN and concentrated in vacuo without heating to a brown syrup.This residue was dissolved in EtOAc and extracted (carefully) threetimes with saturated NaHCO₃. The aqueous fractions were combined,treated with solid NaHCO₃ to ensure pH of 8, and backwashed twice withEtOAc. The EtOAc fractions were combined, dried over Na₂SO₄, filtered,concentrated, and subjected to high vacuum to afford 24.83 g of 5.

A mixture of 1.06 g (2.00 mmol) of 4 and 1.01 g (2.00 mmol) of 5 wasdissolved in mL of anhydrous CHCl₃. Added 0.54 g (4.0 mmol) of HOBT,0.46 g (2.4 mmol) of EDC, and 0.33 mL (3.0 mmol) of N-methyl morpholineand stirred the resultant suspension at room temperature under Ar. Thereaction became an orange solution and, after 24 hours, tlc and MS/HPLCshowed it to be complete. The reaction mixture was diluted with CH₂Cl₂and extracted twice with water, twice with saturated NaHCO₃ and oncewith brine. The CH₂Cl₂ fraction was dried over Na₂SO₄, filtered, andconcentrated in vacuo to afford 1.98 g of brown crusty foam that wassubjected to flash silica gel chromatography (1:1 hexane/EtOAc to 1:3hexane/EtOAc). Obtained 1.71 g (89%) of 6.

A solution of 0.33 g (0.346 mmol) of 6 in a mixture of 2.1 mL of THF and1.4 mL of MeOH was treated with 0.70 mL of 2.0 M LiOH (aqueous) (1.4mmol) and the resultant mixture was stirred at room temperature for 8hours. The reaction mixture was cooled in an ice bath then treated with1.4 mL of cold 1.0 M HCl (aqueous) to neutralize. The quenched reactionwas partially concentrated in vacuo to an aqueous slurry that wasextracted with EtOAc until tlc showed the extraction was complete. TheEtOAc layer was dried over Na₂SO₄, filtered, and concentrated to afford0.321 g (99%) of 7.

A mixture of 7 (0.798 g, 0.849 mmol), HOBT (0.224 g, 1.70 mmol), EDC(0.278 g, 1.70 mmol), and NH₄Cl (0.099 g, 1.7 mmol) was dissolved in 8mL of DMF under an Ar atmosphere. DIEA (0.59 mL, 3.4 mmol) was added andthe reaction mixture stirred at room temperature for 8 hours. Themixture was poured into a mixture of 5 mL 1 N HCl and extracted withEtOAc. The organic phase was washed with H₂O and brine, dried (Na₂SO₄)and the solvent evaporated to yield 0.729 g (91%) of 8 that was usedwithout further purification in the subsequent reaction.

Compound 8 (0.900 g, 0.96 mmol) was stirred at room temperature in 4.5mL of a 33% solution (v/v) of TFA/CH₂Cl₂ for 1.5 hours. Et₂O was added,and the solid filtered or the mixture centrifuged and the solventdecanted. The resultant solid was triturated with Et₂O and dried toyield 0.75 g (82%) of mono-TFA salt 9 as a white powder.

A mixture of 0.321 g (0.341 mmol) of 7 and 0.286 g (0.341 mmol) of 9(free based from its TFA salt by extraction between saturated NaHCO₃ andEtOAc) was dissolved in 15 mL of anhydrous CHCl₃. Added 0.092 g (0.68mmol) of HOBT, 0.079 g (0.41 mmol) of EDC, and 0.056 mL (0.51 mmol) ofN-methyl morpholine and stirred the resultant suspension at roomtemperature under Ar. The reaction became a yellow solution and, afterhours, tlc and MS/HPLC showed it to be complete. The reaction mixturewas diluted with CH₂Cl₂ and extracted twice with water, twice withsaturated NaHCO₃, once with 10% citric acid (aqueous), and twice withbrine. The CH₂Cl₂ fraction was dried over Na₂SO₄, filtered, andconcentrated in vacuo to afford 0.607 g of beige wax that was subjectedto flash silica gel chromatography (CH₂Cl₂ to 97:3 CH₂Cl₂/MeOH).Obtained 0.411 g (68%) of 10 as a beige solid.

Compound 10 (0.411 g, 0.233 mmol) was introduced to a 100 mL roundbottom flask that was equipped with a ground glass stopper (secured by aKeck clamp) and treated with 5 mL of a cold 10% solution (v/v) of TFA inCH₂Cl₂. The resultant brick red solution was allowed to warm to roomtemperature. The reaction was followed by tlc and all of 10 was consumedafter 24 hours. The reaction was diluted with CH₃CN and concentrated invacuo without heating to a brown syrup. This residue was dissolved inCH₂Cl₂ and extracted three times with saturated NaHCO₃. The aqueousfractions were combined and backwashed twice with CH₂Cl₂. The CH₂Cl₂fractions were combined, dried over Na₂SO₄, filtered, and concentratedto afford 0.394 g (101% of theoretical) of a sample of crude 11 as abeige amorphous solid. This crude product was used without furtherpurification in the subsequent reaction.

Introduced 0.197 g (assumed 0.118 mmol) of the crude sample of 11 to a250 ml round bottom flask that was equipped with an adapter containing athree way stopcock to which a balloon was attached. Dissolved 11 in amixture of 5 mL of THF and 5 mL of MeOH, added 0.59 ml of 1.0 M HCl(aqueous), and bubbled Ar through the reaction solution for 15 minutes.Carefully added a small scoop of 10% Pd/C and exposed the reaction to H₂at atm via the balloon. Stirred vigorously, followed the reaction byMS/HPLC, and recharged the balloon with H₂ as needed. After 60 hours,the completed reaction was suctioned filtered through Celite using MeOHto assist transfer and to wash the collected solids. The filtrate wasconcentrated to afford 0.150 g of beige waxy solid. The final productwas purified by reverse phase column chromatography.

Synthesis of Compound 12

Step 1: Starting material 5-nitro salicylic acid (40 g, 0.218 mol) wasdissolved in 220 mL of DMSO followed by addition of KCO₃ (151 g, 1.09mol). Methyl iodide (136 mL, 2.18 mol) was added to the solution. Thereaction mixture was heated to 60° C. and stirred (mechanical stir)overnight. Ethyl acetate (6 L) was added to the reaction mixture in 4portions to completely dissolve the desired product. The suspension wasfiltered to remove solid. The organic layer was washed with 1N HCl,saturate NaCl and water, dried over Na₂SO₄. The solvent was removed byrotovap. Yield: 45.7 g, 99%.

Steps 2 and 3: To the solution of ester compound 1 (10 g, 47.36 mmol) in4:1 methanol/acetonitrile (250 mL) there was added 2 N LiOH (47.4 mL,94.7 mmol). The resulting solution was stirred at room temperature untilno starting material remained (ca. 3 hours). The solution was thenacidified to pH=4-5 with cold HCl, extracted with EtOAc-MeOH (10% MeOH)five times. The combined organic layers were washed with brine, driedover Na₂SO₄, filtered and concentrated to give 9.5 g of the acid.

The product from the hydrolysis was dissolved 120 mL of MeOH-THF (5:1),and Pd—C (10% wt. 1.7 g 94.7 mmol) was introduced. The resulting mixturewas charged hydrogen by a balloon, and stirred at room temperatureovernight. The catalyst was filtered with celite and solvent was removedunder reduced pressure. The product was dried under vacuum overnight.Yield: 8.3 g, 100%.

Step 4: Fmoc-D-Arg(Pbf)-Opf (25 g, 30.68 mmol), compound 2 (5.64 g,33.75 mmol) were dissolved in anhydrous DMF (85 mL). HOAT (30.78 mmol in61.4 mL of DMF) and DIEA (6.41 ml, 36.82 mmol) were added to thesolution at 0° C. under Ar. The solution was warmed up to roomtemperature and stirred overnight. The solvent was removed on a rotovap.The product was purified by flash column using DCM: MeOH (25:1 to 15:1).Purification was done on a C18 reverse phase flash column as well usingAcCN:water. Yield: 15.4 g, 57%.

Step 5: The Fmoc protected compound 3 (6.74 g, 8.45 mmol), EDC (3.24 g,16.9 mmol), HOBt (2.28 g, 16.9 mmol), DIEA (4.36 g, 33.8 mmol) and NH₄Cl(0.904 g, 16.9 mmol) were mixed and dissolved in anhydrous DMF (35 mL),and stirred for 6 hours at 0° C. The solution was diluted with EtOAc andwashed with 10% citric acid, sat. NaHCO₃ and NaCl. The final product waspurified on a flash column with DCM:MeOH (35:1 to 20:1). Yield 3.77 g,56%.

Steps 6 and 7:

Fmoc deprotection: The amide 4 (3.7 g, 4.6 mmol) was treated with Et₂NH(7.76 ml) in 60 mL of THF at 0° C. for 6 hours. After the liquid isremoved under vacuum, the solid was redissolved in AcCN:MeOH (1:1) andthe solvent was remove on a rotovap. This process was repeated two timesto remove any residual Et₂NH. The resulting off-white frothy materialwas triturated with diethyl ether (6×40 mL) and the resulting thickliquid was dried on a vacuum pump overnight to afford the puredeprotected amine.

The deprotected amine was dissolved in 20 mL of anhydrous DMF. Compound3 (3.69 g, 4.62 mmol), HATU (1.755 g, 4.62 mmol), HOAT (4.62 mmol) andDIEA (1.49 g, 11.57 mmol) were dissolved in 30 mL of anhydrous DMF andadded to a solution of the deprotected amine in 10 mL of DMF. Thereaction mixture was stirred at room temperature for 3 hours. Thesolution was diluted with 200 mL of DCM and washed with 10% citric acid,sat. NaHCO₃, brine and water. The organic layer was concentrated on arotovap. Final product was purified on a C18 reverse phase column usinga gradient of AcCN/water. Yield: 4.72 g, 75%.

Steps 8 and 9:

Fmoc deprotection: The amide 5 (4.5 g, 3.32 mmol) was dissolved in 23 mLof DMF and cooled to 0° C. Et₂NH (5.1 g) was added to the solutiondropwise under Ar. The resulting solution was stirred at 0° C. for 3.5hours. After the liquid is removed under vacuum, the deprotected aminewas triturated and washed with EtOAc-Hexanes (3:1) three times to affordpure compound.

After the solid was dried under vacuum, it was coupled with compound 3using HOAT, HATU, DIEA in DMF for 4 hours. (procedure and reactant arethe same as the procedure for synthesize compound 5). The product waspurified using a C18 reverse phase column with gradient of AcCN/water.Yield: 1.21 g, 20%

Steps 10 and 11: Compound 7 was synthesized from 0.68 mmol of 6 usingthe same procedures (Fmoc deprotection and coupling) to synthesizecompound 6. After work up, the crude compound 7 was used for next stepwithout purification.

Steps 12 and 13: The amide 7 (1.68 g, 70% purity) was treated with Et₂NH(0.767 g) in 10 mL of DMF at 0° C. for 1.5 hours. The deprotected aminewas worked up as usual. The Pbf group was removed by a treatment of 250mL of TFA cocktail (95% TFA, 2.5% water and 2.5% triisopropylsilane) for1 hour. The reaction mixture was concentrated on a rotovap to its halfvolume and cooled with ice water bath and triturated with 400 mL of coldMTBE. The solid was washed twice with cold MTBE and dried under vacuum.The final product was purified by prep HPLC on a C4 reverse phase columnusing a gradient of AcCN:water (with 0.1% TFA). Yield 0.379 g, 43%.

The Synthesis of Salicylamides: (Compounds 7-85, 89-102, 107-146)

For salicylamides with the same repeating unit, they are made usingprocedures that at similar to the synthesis of compound 12 and 89. Forsalicylamides with different building units, they were made via solidphase synthesis which is described as following:

Solid phase synthesis procedure for salicylamides: The synthesis wascarried at 0.2 mmol scale using Fmoc chemistry. PAL-PEG resin was usedfor amide oligomers, and Wang resin was used for acid oligomers. Thecoupling reagents are HATU/HOAT with DIEA, solvent was DMF. Piperidine(20% in DMF) was used for Fmoc removal. The cleavage and finaldeprotection were performed using 95% TFA with 5% TIS. The finalproducts were purified on RP-HPLC.

Synthesis of Labaled Compound 121

The compound was made via solid phase synthesis. The last building blockfor the solid phase synthesis (3) was made by the following procedure:

Step 1: L-D4-Lysine (12.4 mmol) was dissolved in 36 mL of water/dioxane(1:1). Boc₂O (31 mmol) was added to the solution, followed by 12.7 mL of1N NaOH. The reaction mixture was stirred for 18 hours before more Boc₂O(9.3 mmol), 1N NaOH (6.5 mL) and dioxane (6 mL) were added. The reactionwas stirred for another 18 hours. The pH of the solution was adjusted to2-3 with KHSO₄ while cooled with ice bath. The product was extracted byEtOAc for 4 times. The organic layer was dried and concentrated to asolid. The product was used for next step without purification.

Step 2: Product from step 1 (1, 9 mmol) was dissolved in 130 mL ofchloroform. To the solution were added 9 mmol of methyl5-amino-2-methoxybenzoate, HOBT (18 mmol), EDC (10.8 mmol) and 1.5 mL ofn-methyl morpholine. The reaction mixture was stirred overnight. Thesolution was diluted with DCM and washed with water. The aqueous layerwas extracted twice with DCM. The combined organic layer was washed withsat. NaHCO₃ and brine, and dried and concentrated to a solid. Theproduct was used for the next step without purification.

Step 3: The product from step 2 (2, 8.37 mmol) was dissolved in 50 mL ofTHF/33 mL of MeOH. LiOH (2N, 16.75 mL) was added to the solution. Thereaction mixture was stirred overnight. While cooled with ice bath, thesolution was neutralized with 1N HCl to pH 6-7. The product wasextracted by EtOAc. After the solvent was removed, the product was driedunder vacuum.

Example 2 Irradiated Hamster Cheek Pouch Model of Oral Mucositis

In the irradiated hamster cheek pouch model of oral mucositis, thehamster cheek pouch is everted and irradiated to produce a localizedmucositis. The progression and resolution of mucositis in the hamstermodel is very similar to that observed in the human condition and themodel has been validated clinically with respect to dosing schedules oftherapeutic agents (Murphy et al., Clin. Cancer Res., 2008, 14,4292-4297; Alvarez et al., Clin. Cancer Res., 2003, 9, 3454-3461; andSchuster et al., J. Clin. Oncol., 2006, 24, 6537). Briefly, on day 0,all animals were given an acute radiation dose directed to their leftbuccal cheek pouch. Test articles were applied topically to the leftpouch three times per day from day 0 to day 20 and mucositis wasevaluated clinically starting on day 6, and continued on alternate daysuntil day 20. Study endpoints were mucositis score, weight change andsurvival. Mucositis was scored visually by comparison to a validatedphotographic scale. The scale ranges from 0 for normal, to 5 for severeulceration. The clinical mucositis score of 3 in hamsters indicates thepresence of an ulcer. In terms of the syndrome, it is believed that thedose-limiting chemotherapeutic- or radiation-induced pain is associatedwith frank ulceration; therefore a compound that prevents ulceration inthe model might have utility in the clinical setting.

To evaluate mucositis severity, animals were anesthetized with aninhalation anesthetic, and the left cheek pouch everted. Mucositis wasscored visually by comparison to a validated photographic scale. Thescale ranges from 0 for normal, to 5 for severe ulceration. Indescriptive terms, this scale is defined as follows:

Mucositis Scoring

Score: Description: 0 Pouch completely healthy. No erythema orvasodilation. 1 Light to severe erythema and vasodilation. No erosion ofmucosa. 2 Severe erythema and vasodilation. Erosion of superficialaspects of mucosa leaving denuded areas. Decreased stippling of mucosa.3 Formation of off-white ulcers in one or more places. Ulcers may have ayellow/gray appearance due to pseudomembrane formation. Cumulative sizeof ulcers should equal about ¼ of the pouch. Severe erythema andvasodilation. 4 Cumulative size of ulcers should equal about ½ of thepouch. Loss of pliability. Severe erythema and vasodilation. 5 Virtuallyall of pouch is ulcerated. Loss of pliability (pouch can only partiallybe extracted from mouth.

A score of 1-2 is considered to represent a mild stage of injury,whereas a score of 3-5 is considered to indicate moderate to severemucositis. In terms of the syndrome, it is believed that thedose-limiting chemotherapeutic- or radiation-induced pain is associatedwith frank ulceration; therefore a compound that prevents ulceration inthe model might have utility in the clinical setting. In the hamstermodel, a clinical mucositis score of 3 indicates the presence of anulcer and the duration of scores of 3 or greater is used as a primarymeasurement of efficacy in mucositis treatment. Ulceration is the pointin the development of mucositis where the physical integrity of the oralmucosa is breached. In the clinic, a patient presenting with severe oralulcerations may require hospitalization for analgesic, narcotic and/orantibiotic therapies or fluid support.

On day 0, all animals were given an acute radiation dose directed totheir left buccal cheek pouch. This was accomplished by anesthetizingthe animals and everting the left buccal pouch, while protecting therest of the animals with a lead shield. Test agents were appliedtopically to the left buccal pouch three times per day from day 0 to day20. Mucositis was evaluated clinically starting on day 6, and continuedon alternate days until day 28. Study endpoints were mucositis score,weight change and survival. Mucositis was scored visually by comparisonto a validated photographic scale. No treatment-related deaths wererecorded throughout the study. The mean daily percent weight gains weresimilar in all groups and there were no apparent toxicities in any ofthe test agent treatment groups. Differences between the ulcerativeseverity in controls and the treated groups were assessed in two ways.First, mean daily mucositis scores for each group at each time-pointwere compared with the untreated control group using the Mann-WhitneyRank-sum analysis. For Compound X, robust efficacy was observed in the1, 3 and 10 mg/ml groups by Day 12 through Day 28. At 0.3 mg/ml,efficacy was partial early in the treatment period. The presence ofKleptose in the vehicle or with 1 mg/kg Compound X did not significantlyimpact the response.

Alternately, ulcerative severity differences between control andtreatment groups were assessed by the comparison of the number of dayswith an ulcer (i.e., a score of 3 or higher) using a chi-squared (χ2)test. There were statistically significant improvements (p<0.001) in themucositis scores of the hamsters in the groups treated with Compound Xat 1, 3 and 10 mg/ml/dose. In the vehicle control group, hamsters had aclinical score that was ≧3 for 42.7% of the treatment days. However, inhamsters treated with Compound X, maximum reductions to <5% of treatmentdays with a clinical score ≧3 were achieved at 1, and 10 mg/ml/dose.These results far exceed the target reduction of 30% in mucositisseverity that is suggested to be predictive for clinical efficacy.

Example 3 Evaluation of Compound X in a Fractionated Radiation-InducedOral Mucositis Model in Hamsters

Seventy (70) male Syrian Golden Hamsters were used in this example.Mucositis was induced using a combination of fractionated radiation andcisplatin. Cisplatin was administered on Days 0 and 6 at a dose of 5mg/kg by i.p. injection. Each hamster was administered a total radiationdose of 60 Gy directed to their left buccal cheek pouch split into eightequal fractions of 7.5 Gy provided on Days 0, 1, 2, 3, 6, 7, 8 and 9.Radiation was generated with a 160 kilovolt potential (15-ma) source ata focal distance of 50 cm, hardened with a 0.35 mm Cu filtration system.Irradiation targeted the left buccal pouch mucosa at a rate of 2.0Gy/minute. Prior to irradiation, animals were anesthetized with an i.p.injection of ketamine (160 mg/mL) and xylazine (8 mg/mL). The leftbuccal pouch was everted, fixed and isolated using a lead shield. Testmaterials were administered topically to the left cheek pouch threetimes daily, as detailed in Table 3 at a dose of 3 mg/mL in a volume of0.5 mL per dose, either on the days of radiation (Days 0-3, 6-9), thedays on which radiation was not administered (−1, 4, 5 and 10), Days0-12 or Days 0-35. Mucositis in the left cheek pouch was evaluatedclinically starting on Day 7, and continuing on alternate days until Day35. On Day 35, all animals were euthanized by CO₂ inhalation and deathwas confirmed by monitoring heartbeat in accordance with USDAguidelines.

TABLE 3 Number of Dose Group Animals Treatment volume Dose Schedule 1 10male Saline 0.5 mL Days 0-35 2 10 male Vehicle tid topical 0.5 mL Days0, 1, 2, 3, 6, 7, 8 & 9 3 10 male Vehicle tid topical 0.5 mL Days 0-35 410 male Compound X, 0.5 mL Days 0, 1, 2, 3, 6, 7, 3 mg/mL 8 & 9 tidtopical 5 10 male Compound X, 0.5 mL Days 0 through 12 3 mg/mL tidtopical 6 10 male Compound X, 0.5 mL Days 0-35 3 mg/mL tid topical 7 10male Compound X, 0.5 mL Days −1, 4, 5, 10 3 mg/mL tid topical

The mucositis score, weight change and survival were measured throughoutthe study. For the evaluation of mucositis, the animals wereanesthetized with an inhalation anesthetic, and the left pouch everted.Mucositis was scored visually by comparison to a validated photographicscale, ranging from 0 for normal, to 5 for severe ulceration (asdescribed above in Example 2). A score of 1-2 is considered to representa mild stage of the disease, whereas a score of 3-5 is considered toindicate moderate to severe mucositis. Following visual scoring, adigital image was taken of each animal's mucosa using a standardizedtechnique. At the conclusion of the experiment, images were randomlynumbered and scored by two independent trained observers graded thephotographs in blinded fashion using the above-described scale (blindedscoring).

The grade of mucositis was scored, beginning on day 7, and for everysecond day thereafter, through and including day 35. The effect onmucositis of each drug treatment compared to placebo was assessedaccording to the following parameters: the difference in the number ofdays hamsters in each group had ulcerative (score ≧3) mucositis and therank sum differences in daily mucositis scores.

On each evaluation day, the number of animals with a blinded mucositisscore of ≧3 in each drug treatment group was compared to the controlgroup. Differences were compared on a cumulative basis and statisticalsignificance was determined by chi-square analysis. Efficacy, in thisanalysis, is defined by a significant reduction in the number of daysthat a group of animals had ulcerations (scores ≧3) when compared to thecontrol group.

For each evaluation day the scores of the control group were compared tothose of the treated groups using non-parametric rank sum analysis.Treatment success was considered as a statistically significant loweringof scores in the treated group on 2 or more days from day 6 to day 28.

All animals were weighed daily and their survival recorded to assesspossible differences in animal weight among treatment groups as anindication for mucositis severity and/or possible toxicity resultingfrom the treatments. No deaths were observed during this study.

The saline vehicle-treated control hamsters gained an average of 48.4%of their starting weight during the study. Hamsters in the group treatedwith Kleptose vehicle on Days 0-3 and Days 6-9 gained an average of57.0% of their starting weights during the study. Hamsters in the groupstreated with Kleptose vehicle on Days 0-3 and Days 6-9 gained an averageof 49.5% of their starting weights respectively during the study.Hamsters in the groups treated with Compound X in Kleptose based vehicleon Days 0-3 and 6-9 or Days 0-12 gained 44.5% and 48.7% of theirstarting weights, respectively. Hamsters in the groups treated withCompound X in Kleptose based vehicle on Days 0-35 or Days—1, 4, 5, and10 gained 47.6% and 46.9% of their starting weights, respectively.

The maximum mean mucositis observed in the saline vehicle control groupwas 3.2, which occurred on Days 17, 19 and 21. The group treated withKleptose vehicle on Days 0-3 and 6-9 had a peak mucositis score of 3.2on Day 19 and the group treated with Kleptose vehicle on Days 0-35 had apeak mucositis score of 3.1 on Day 21. The group treated with Compound Xat 3 mg/mL (in Kleptose vehicle) on Days 0-3 and 6-9 had a peak meanmucositis score of 3.1 on Day 19. The group treated with Compound X onDays 0-12 had a maximum mean mucositis score of 3.1 on Days 19, 21 and23. The group treated with Compound X on Days 0-35 had a maximum meanmucositis score of 2.1 on Days 19 and 21. The group treated withCompound X on Days—1, 4, 5, and 10 had a peak mean mucositis score of3.1 on Day 19.

In the saline vehicle control group, the percentage of animal days witha score of 3 or higher was 54.7%. In the groups treated with theKleptose vehicle on Days 0-3 and 6-9 or Days 0-35, the percentage ofanimal days with a score of 3 or higher was 46.7% and 56.0%,respectively. In the group treated with Compound X on Days 0-3 and 6-9,the percentage of animal days with a score of 3 or higher was 58.0%. Inthe group treated with Compound X on Days 0-12, the percentage of animaldays with a score of 3 or higher was 58.0%. In the group treated withCompound X on Days—1, 4, 5, and 10, the percentage of animal days with ascore of 3 or higher was 48.0%. In the group treated with Compound X onDays 0-35, however, the percentage of animal days with a score of 3 orhigher was 3.3%, which was significantly lower than the saline controlgroup and the Kleptose vehicle group dosed on the same days (p<0.001 forboth comparisons).

An analysis of the severity of mucositis was performed using theMann-Whitney rank sum analysis to compare the scores for each treatmentgroup to the controls on each day of the analysis. In this analysis, 2days of significant reduction in the mucositis score are generallyrequired before it is regarded as meaningful.

The group treated with Compound X at 3 mg/mL tid from Day 0 until Day 35had statistically significant reductions in mucositis scores on Days 11(p=0.002), 13 (p=0.023) and 15-35 (p<0.001 for all 11 days) whencompared to the saline control group. When compared to the Kleptosecontrol group, statistically significant reductions in mucositis scoreswere observed on Days 17, 19, 21, 23, 25, 27, 29, 31, 33 and 35 (p<0.001for all days).

When compared to the saline control group, the two Kleptose vehiclebased groups had significant reductions in mucositis scores on Days 11,13 and 15 (for the groups dosed on Days 0-3 and 6-9), or Days 11 and 15(for the Group dosed on Days 0-35), and a significant increase inmucositis scores on Day 27. This pattern was also observed in the groupstreated with Compound X on Days 0-3 and 6-9 or Days 0-12. The similarityof response in these four groups suggests that the Kleptose vehicle mayslightly delay both the onset of severe mucositis and possibly alsodelay the resolution of oral mucositis.

The group treated with Compound X on Days—1, 4, 5 and 10 hadstatistically significant reductions in mucositis scores on Days21(p=0.018), 23(p=0.040), 25(p=0.040), 33(p=0.036), and 35(p=0.036).This pattern of improvement in mucositis scores differs markedly fromthe patterns observed in the groups treated on the days of radiation(0-3, 6-9), which Kleptose vehicle alone throughout the study (Days0-35), or with Compound X on Days 0-12.

At least 90% of the saline control and the Kleptose vehicle treatedanimals developed ulcerative mucositis by Day 17, which persisted untilDay 25 in the saline controls and Day 27 in the Kleptose vehicle groups.The groups treated with Compound X on Days 0-3 and 6-9 or Days 0-12 hada 100% ulceration rate on Day 17, which continued at until Day 27 in thegroup treated from Day 0 to Day 12, and until Day 29 in the grouptreated on Days 0-3 and 6-9. The group treated with Compound X on Days0-35 had a 10% ulceration rate on Days 15-23. This represented a singlehamster with an ulcer that persisted for 8 days. No other ulcers wereobserved in this group. The group treated with Compound X on Days—1, 4,5, and 10 had a 100% ulceration rate on Day 19 only.

Several conclusions can be drawn from this study, including: 1) therewas no evidence of any adverse reaction to treatment with Compound X,administered three times daily by topical application to the left buccalpouch for the duration of the study; 2) Compound X administeredthroughout the study reduced the incidence of ulcerative oral mucositisfrom 54.7% in the saline controls to 3.3% in the group treated withCompound X from Day 0 until Day 35; 3) the group treated with Compound Xfrom Day 0 to Day 35 had statistically significant reductions inmucositis scores on Days 11 (p=0.002), 13 (p=0.023), and 15, 17, 19, 21,23, 25, 37, 29 31, 33 and 35 (p<0.001 on all days); and 4) thepercentage of hamsters in which an ulcer formed during the study wasreduced from 100% in the saline and vehicle controls to 10% in the grouptreated with Compound X from Day 0 to Day 35.

Example 4 Evaluation of the Impact of Compound X on Tumor Growth andResponse to Therapy in the FaDu Human Head and Neck Cancer Grown as aXenograft

Ninety (90) male nude mice (nu/nu) were divided into nine (9) groups often (10) mice per group. To ensure that a sufficient number oftumor-bearing animals were available for this study, a total of 100 micewere inoculated s.c. in the flank with 1×10⁶ FaDu cells. FaDu (HTB-43)human head and neck cancer cells were obtained from ATCC. These cellswere grown in EMEM medium supplemented with 10% Fetal Calf Serum (FCS),1% penicillin and streptomycin, and 2 mM L-Glutamine. Cells weresub-cultured by removing the medium, rinsing twice with sterile calcium-and magnesium-free phosphate buffered saline (PBS) and adding 1 to 2 mLof 0.25% trypsin/0.03% EDTA solution. The flask was incubated at 37° C.until cells detached. Cells were then sub-cultured at a ratio of 1:3.When tumors reached an average volume of approximately 100 mm³, animalswere randomized by tumor volume and treated with radiation,chemotherapy, or Compound X, or combinations of Compound X and eitherradiation or chemotherapy, as shown in Table 4. Tumors were measuredonce every two days with micro-calipers, and tumor volume was calculatedas (length×width×width)/2. Where animals were euthanized for tumorvolume exceeding the maximum permissible by IACUC rules (1500 mm³) ortumor ulceration, the last measurement was carried forward incalculations of mean tumor volume.

TABLE 4 Number of Dosing Schedule Group # Animals Inoculum* Treatment(IP) (Days) 1 10 Male FaDu Vehicle Control QD, Days 0-28 1 × 10⁶ cells 210 Male FaDu Compound X 0.06 mg/kg QD, Days 0-28 1 × 10⁶ cells 3 10 MaleFaDu Compound X 0.3 mg/kg QD, Days 0-28 1 × 10⁶ cells 4 10 Male FaDuRadiation focal to tumor Days 0-3, 6-9 1 × 10⁶ cells 8 fractions of1.25Gy/10Gy total Days 0-28 Vehicle 5 10 Male FaDu Radiation focal totumor Days 0-3, 6-9 1 × 10⁶ cells 8 fractions of 1.25Gy/10Gy total QD,Days 0-28 Compound X 0.06 mg/kg 6 10 Male FaDu Radiation focal to tumorDays 0-3, 6-9 1 × 10⁶ cells 8 fractions of 1.25Gy/10Gy total QD, Days0-28 Compound X 0.3 mg/kg 7 10 Male FaDu Cisplatin 5 mg/kg Days 0, 14 1× 10⁶ cells Vehicle QD, Days 0-28 8 10 Male FaDu Cisplatin 5 mg/kg Days0, 14 1 × 10⁶ cells Compound X 0.06 mg/kg QD, Days 0-28 9 10 Male FaDuCisplatin 5 mg/kg Days 0, 14 1 × 10⁶ cells Compound X 0.3 mg/kg QD, Days0-28

All animals were weighed every day and their survival recorded, toassess possible differences in animal weight among treatment groups asan indication of possible toxicity resulting from the treatments. Anyanimals exhibiting a loss of >20% of starting weight during the courseof the study were euthanized. Any animals whose tumor grew to over 1500mm³ were also euthanized.

No animal deaths occurred as a direct result of treatment during thecourse of this study. A total of 65 animals were euthanized during thecourse of the study, 39 of these were due to the tumor in these animalsexceeding the maximum volume (1500 mm³) allowed by IACUC and theremaining 26 were due to ulceration of the tumor and the resultinghealth risk posed by the wound. In the groups that did not receiveeither radiation or chemotherapy, 70% of the animals were euthanized fortumor size (range 6 of 10 to 8 of 10), 16.7% of the animals wereeuthanized for tumor ulceration (range 1 of 10 to 2 of 10), and 13.3% ofthe animals survived (range 0 to 2). In the groups receiving radiationtherapy, 37.7% of the animals were euthanized for tumor size (range 3 of10 to 4 of 10), 43.3% of the animals were euthanized for tumorulceration (range 4 of 10 to 5 of 10), and 20% of the animals survived(range 1 to 3). In the groups receiving cisplatin chemotherapy, 23% ofthe animals were euthanized for tumor size (range 2 of 10 to 3 of 10),26.7% of the animals were euthanized for tumor ulceration (range 2 of 10to 4 of 10), and 50% of the animals survived (range 4 to 6). In thegroups receiving vehicle 43.3% of the mice were euthanized for tumorvolume in excess of 1500 mm³, compared to 46.7% in groups treated withCompound X at 0.06 mg/kg, and 40% in groups treated with Compound X at0.3 mg/kg. Similarly, 30% of the mice treated with vehicle wereeuthanized for tumor ulceration, compared to 33.3% in groups treatedwith Compound X at 0.06 mg/kg, and 23.3% in groups treated with CompoundX at 0.3 mg/kg. Survival at Day 29 in the vehicle groups was 26.7%,compared to 20% in groups treated with Compound X at 0.06 mg/kg, and36.7% in groups treated with Compound X at 0.3 mg/kg.

The mice receiving vehicle only had a mean weight gain of 5.9% by Day15, when the first animal in the study was euthanized, and had gained anaverage of 15.2% of their starting weight by the end of the study. Themice receiving Compound X at 0.06 mg/kg had a mean weight gain of 9.1%by Day 15, and had gained an average of 16.1% of their starting weightby Day 27 when the last animal in this group was euthanized. Micereceiving Compound X at 0.3 mg/kg had a mean weight gain of 4.8% by Day15, and had gained an average of 12.9% of their starting weight by theend of the study. The mice receiving vehicle in addition to radiationtherapy had a mean weight gain of 10.3% by Day 15, and had gained anaverage of 0.6% of their starting weight by the end of the study. Themice receiving radiation therapy plus Compound X at 0.06 mg/kg had amean weight gain of 4.2% by Day 15, and had gained an average of 13.4%of their starting weight by the end of the study. Mice receivingradiation therapy and Compound X at 0.3 mg/kg had a mean weight gain of6.5% by Day 15, and had gained an average of 14.1% of their startingweight by the end of the study. The mice receiving vehicle in additionto cisplatin chemotherapy had a mean weight gain of 7.2% by Day 15, whenand had gained an average of 13.0% of their starting weight by the endof the study. The mice receiving cisplatin chemotherapy plus Compound Xat 0.06 mg/kg had a mean weight gain of 0.8% by Day 15, and had gainedan average of 10.8% of their starting weight by the end of the study.Mice receiving cisplatin chemotherapy and Compound X at 0.3 mg/kg had amean weight gain of 8.4% by Day 15, and had gained an average of 18.7%of their starting weight by the end of the study.

The mean tumor volume for the vehicle control group increased from 96mm³ on Day 1 to 928 mm³ on Day 15, and to 1096 mm³ at the end of thestudy. In the group treated with Compound X at 0.06 mg/kg, the meantumor increased from 102 mm³ on Day 1 to 904 mm³ on Day 15, and to 2234mm³ on Day 27 when the final animal in this group was euthanized. In thegroup treated with Compound X at 0.3 mg/kg, the mean tumor increasedfrom 96 mm³ on Day 1 to 869 mm³ on Day 15, and to 1002 mm³ at the end ofthe study. The mean tumor volume for the group that received radiationplus vehicle increased from 102 mm³ on Day 1 to 652 mm³ on Day 15, anddecreased by 11 mm³ at the end of the study. In the group treated withradiation plus Compound X at 0.06 mg/kg, the mean tumor increased from96 mm³ on Day 1 to 596 mm³ on Day 15, and to 1027 mm³ at the end of thestudy. In the group treated with radiation plus Compound X at 0.3 mg/kg,the mean tumor increased from 108 mm³ on Day 1 to 616 mm³ on Day 15, andto 1376 mm³ at the end of the study. The mean tumor volume for the groupthat received cisplatin plus vehicle increased from 100 mm³ on Day 1 to652 mm³ on Day 15, and decreased to 302 mm³ at the end of the study. Inthe group treated with cisplatin plus Compound X at 0.06 mg/kg, the meantumor increased from 100 mm³ on Day 1 to 518 mm³ on Day 15, anddecreased to 338 mm³ at the end of the study. In the group treated withcisplatin plus Compound X at 0.3 mg/kg, the mean tumor increased from104 mm³ on Day 1 to 564 mm³ on Day 15, and decreased to 510 mm³ at theend of the study. The second dose of cisplatin, given to the final threegroups on Day 21 had a noticeable impact on tumor volume in thesegroups, however while some of the tumors responded very well to thecisplatin, others did not show a noticeable response and a third subsetulcerated, causing the data to be relatively erratic from approximatelyDay 22 on.

Further analysis of the tumor volume data was performed by calculatingthe mean area under the curve (AUC) for the tumor volume for each animaland comparing the groups using an ANOVA on ranks test. Due to the impactof animals euthanized for tumor ulceration or volume in excess of 1500mm³, this analysis was performed on data to Day 15 as well as on thefull data set to Day 29. The Day 15 analysis indicated that there werestatistically significant differences between the vehicle control groupand the groups treated with radiation plus Compound X at 0.3 mg/kg(p=0.017), cisplatin plus vehicle (p=0.011), cisplatin plus Compound Xat 0.06 mg/kg (p=0.001), and cisplatin plus Compound X at 0.3 mg/kg(p=0.002).

Example 5 Efficacy of Compound X in Hamster Models of Ulcerative OralMucositis

Marked inhibitory effects were observed in the severity and course ofradiation-induced mucosal injury in hamster models of ulcerativemucositis after topical administration of Compound X. In both acute andfractionated radiation hamster models, topical applications of CompoundX as an oral rinse 3 times daily over 28 and 35 day treatment regimenssignificantly reduced the daily mean mucositis scores and the number ofdays animals exhibited ulceration. There were no adverse findings inweight gain, general behavior in the home cage, or clinical signsattributed to Compound X in any of the treatment groups. In thefractionated radiation model which better reflects the clinicalsituation for radiation therapy, Compound X significantly reduced thedaily mucositis scores beginning prior to peak mucositis and significantreductions remained evident throughout the remaining course oftreatment. Table 5 below shows the percent reduction of days the animalsexhibited ulceration in the acute and fractionated radiation models withCompound X in comparison to published results for two other agentscurrently under clinical study, SCV-07 and AG013, that were tested innearly identical models. Greater efficacy was achieved with Compound Xin all comparisons.

TABLE 5 % reduction of animal days with OM scores ≧3 Model/CompoundSCV-07 AGO13 Compound X Acute Radiation 68.3%-77.6% 32.8%-40.0%90.6%-95.3% Fractionated Radiation 33.3% Not reported 92.6%

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference (including, but not limitedto, journal articles, U.S. and non-U.S. patents, patent applicationpublications, international patent application publications, gene bankaccession numbers, and the like) cited in the present application isherein incorporated by reference in its entirety.

1. A method of treating mucositis in a mammal comprising administeringto the mammal in need thereof a therapeutically effective amount of acompound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein: each A is,independently, —C═O, —C═S, or CH₂; each D is, independently, O or S;each R¹ is, independently, hydrogen, C₁₋₃alkyl, C₁₋₃alkoxy, halo, orhaloC₁₋₃alkyl; each R² is, independently, hydrogen, C₁₋₃alkyl,C₁₋₃alkoxy, halo, or haloC₁₋₃alkyl; each R³ is, independently, hydrogen,C₁₋₄alkyl, C₁₋₄alkoxy, halo, or haloC₁₋₄alkyl; and each R⁴ is,independently, hydrogen, C₁₋₃alkyl, C₁₋₃alkoxy, halo, or haloC₁₋₃alkyl.2. The method of claim 1 wherein at least one A is —C═O.
 3. The methodof claim 1 wherein at least one D is O.
 4. The method of claim 1 whereineach R¹ is, independently, hydrogen, methyl, methoxy, halo, orhaloC₁₋₃alkyl.
 5. The method of claim 1 wherein at least one R¹ ishydrogen.
 6. The method of claim 1 wherein each R² is, independently,hydrogen, methyl, methoxy, or halo.
 7. The method of claim 1 wherein atleast one R² is hydrogen.
 8. The method of claim 1 wherein each R³ is,independently, methyl, methoxy, halo, or haloC₁₋₃alkyl.
 9. The method ofclaim 1 wherein each R³ is, independently, haloC₁₋₃alkyl.
 10. The methodof claim 1 wherein at least one R³ is trifluoromethyl.
 11. The method ofclaim 1 wherein each R⁴ is, independently, hydrogen, methyl, methoxy,halo, or haloC₁₋₃alkyl.
 12. The method of claim 1 wherein each R⁴ is,independently, hydrogen, methyl, methoxy, or halo.
 13. The method ofclaim 1 wherein at least one R⁴ is hydrogen.
 14. The method of claim 1wherein: each A is, independently, —C═O or —C═S; each D is,independently, O or S; each R¹ is, independently, hydrogen, methyl,methoxy, halo, or halomethyl; each R² is, independently, hydrogen, halo,or halomethyl; each R³ is, independently, methyl, ethyl, methoxy,ethoxy, halo, halomethyl, or haloethyl; and each R⁴ is, independently,hydrogen, methyl, ethyl, methoxy, ethoxy, halo, halomethyl, orhaloethyl.
 15. The method of claim 1 wherein: each A is —C═O; each D isO; each R¹ is, independently, hydrogen, halo, or halomethyl; each R² is,independently, hydrogen or halo; each R³ is, independently, methyl,methoxy, halo, or halomethyl; and each R⁴ is, independently, hydrogen,methyl, methoxy, halo, or halomethyl.
 16. The method of claim 1 wherein:each A is —C═O; each D is O; each R¹ is, independently, hydrogen orhalo; each R² is, independently, hydrogen or halo; each R³ is,independently, methyl, halo, or halomethyl; and each R⁴ is,independently, hydrogen, methyl, halo, or halomethyl.
 17. The method ofclaim 1 wherein: each A is —C═O; each D is O; each R¹ is, independently,hydrogen or halo; each R² is, independently, hydrogen or halo; each R³is, independently, methyl, halo, or halomethyl; and each R⁴ is,independently, hydrogen, methyl, halo, or halomethyl.
 18. The method ofclaim 1 wherein: each A is —C═O; each D is O; each R¹ is, independently,hydrogen or halo; each R² is, independently, hydrogen or halo; each R³is, independently, halo or halomethyl; and each R⁴ is, independently,hydrogen, halo, or halomethyl.
 19. The method according to claim 1wherein the compound of Formula III is,

or a pharmaceutically acceptable salt thereof.
 20. A method of treatingmucositis in a mammal comprising administering to the mammal in needthereof a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: X is O or S; R₁is C₁-C₉ straight or branched chain alkyl, optionally substituted withone or more —NH₂ or —NH—C(═NH)NH₂; Y is a bond or a carbonyl; Z is abond or a carbonyl; R₂ is hydrogen or C₁-C₉ straight or branched chainalkyl optionally substituted with one or more —NH₂ or —NH—C(═NH)NH₂; orR₂ is —X—R₁; R₃ is methylene or

wherein the methylene is substituted with C₁-C₉ straight or branchedchain alkyl, wherein the C₁-C₉ straight or branched chain alkyl isoptionally substituted with one or more —NH₂ or —NH—C(═NH)NH₂; n is2-10; and m is 1 or 2; a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein: X is O or S; Yis O or S; R₁ is H or —C(═O)-A, where A is C₁-C₉ straight or branchedalkyl optionally substituted with one or more —NH₂, —N(CH₃)₂ or—NH—C(═NH)NH₂; R₂ is C₁-C₉ straight or branched alkyl optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂; R₃ isC₁-C₉ straight or branched alkyl optionally substituted with one or more—NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂; and R₄ is H, —B, or —C(═O)—O—B, where Bis C₁-C₉ straight or branched alkyl; a compound chosen from:

or a pharmaceutically acceptable salt thereof; a compound of FormulaIII:

or a pharmaceutically acceptable salt thereof, wherein: each A is,independently, —C═O, —C═S, or CH₂; each D is, independently, O or S;each R¹ is, independently, hydrogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, halo, orhaloC₁₋₃ alkyl; each R² is, independently, hydrogen, C₁₋₃ alkyl, C₁₋₃alkoxy, halo, or haloC₁₋₃ alkyl; each R³ is, independently, hydrogen,C₁₋₄alkyl, C₁₋₄alkoxy, halo, or haloC₁₋₄alkyl; and each R⁴ is,independently, hydrogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, halo, or haloC₁₋₃alkyl; a compound of Formula IV:

or a pharmaceutically acceptable salt thereof, wherein: n=1 to 10; X isO or S; Y is O or S; Z is a bond, C₁-C₉ straight or branched alkyl, or a1,4-cyclohexyl; R₁ is NH₂ or NH-A, where A is C₁-C₉ straight or branchedalkyl, where A is optionally substituted with —NH₂, —N(CH₃)₂ or—NH—C(═NH)NH₂; R₂ is C₁-C₉ straight or branched alkyl, where R₂ isoptionally substituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂;R₃ is C₁-C₉ straight or branched alkyl, where R₃ is optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂; R₄ is H or

a compound of Formula V:

or a pharmaceutically acceptable salt thereof, wherein: n is 2-8; X is abond, O or —O—CH₂—C(═O)—O—, R₁ is -A or —O-A, where A is C₁-C₉ straightor branched alkyl; and R₂ is C₁-C₉ straight or branched alkyl, where R₂is optionally substituted with one or more —NH₂, —N(CH₃)₂, or—NH—C(═NH)NH₂; a compound of Formula VI:

or a pharmaceutically acceptable salt thereof, wherein: n is 2 to 10; R₁is H or

R₂ is C₁-C₉ straight or branched alkyl, where R₂ is optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂; R₃ isC₁-C₉ straight or branched alkyl, where R₂ is optionally substitutedwith one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂; R₄ is OH, NH₂ or

where A is OH or NH₂; a compound of Formula VII:

or a pharmaceutically acceptable salt thereof, wherein: X is C(R⁷)C(R⁸),C(═O), N(R⁹), O, S, S(═O), or S(═O)₂; R⁷, R⁸, and R⁹ are, independently,H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH, CF₃, or aromatic group; R¹ and R²are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH,haloC₁-C₈alkyl, or CN; R³ and R⁴ are, independently, carbocycle(R⁵)(R⁶);each R⁵ and each R⁶ are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy,halo, OH, CF₃, aromatic group, heterocycle, or the free base or saltform of —(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 8; acompound of Formula VIII:

or a pharmaceutically acceptable salt thereof, wherein: X is O or S;each Y is, independently, O, S, or N; each R¹ is, independently, H, 5-or 6-membered heterocycle, or the free base or salt form of—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; or each R¹ is, independently, together with Y a5- or 6-membered heterocycle; each R² is, independently, H, CF₃,C(CH₃)₃, halo, or OH; and each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; acompound of Formula IX:Q-X—Z—X-Q  IX or a pharmaceutically acceptable salt thereof, wherein: Zis

Or phenyl; each Q is, independently,

or —C(═O)—(CH₂)_(b)—NH—C(═NH)—NH₂, where each b is, independently, 1 to4; each X is, independently, O, S, or N; each R¹ is, independently, H,CF₃, C(CH₃)₃, halo, or OH; each R³ is, independently, H, —NH—R²,—(CH₂)_(n)—NH₂, —NH₂, —NH—(CH₂)_(w)—NH₂, or

where each r is, independently, 1 or 2, each w is, independently, 1 to3, and each y is, independently, 1 or 2; each R² is, independently, H,or the free base or salt form of —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; each R⁴is, independently, H, —NH—C(═O)—(CH₂)_(p)—NH—C(═NH)—NH₂ or

where each p is, independently, 1 to 6, and each q is, independently, 1or 2; and each R⁵ is, independently, H or CF₃; a compound of Formula X:

or a pharmaceutically acceptable salt thereof, wherein: G is

each X is, independently, O or S; each R¹ is, independently,

or the free base or salt form of —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; each R²is, independently, H, C₁-C₈alkyl, or the free base or salt form of—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; each R³ is, independently, H, CF₃, C(CH₃)₃, halo,or OH; and each R⁴ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4;provided that the compound is not Compound Y; a compound of Formula XI:

or a pharmaceutically acceptable salt thereof, wherein: each X is,independently, O, S, or S(═O)₂; each R¹ is, independently,—(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴,where each n is, independently, 1 to 4, and each R⁴ is, independently,H, C₁-C₃alkyl, or —(CH₂)_(p)—NH₂, where each p is, independently, 1 or2; each R² is, independently, H, halo, CF₃, or C(CH₃)₃; and each V² isH, and each V¹ is, independently, —N—C(═O)—R³, where each R³ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 4; or each V¹ is H and each V² is,independently, —S—R⁵, where each R⁵ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or apharmaceutically acceptable salt thereof; provided that the compound isnot Compound Z; a compound of Formula XII:

or a pharmaceutically acceptable salt thereof, wherein: each Y is,independently, O, S, or NH; each R¹ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; andeach R² is, independently, H, halo, CF₃, or C(CH₃)₃; a compound ofFormula XIII:

or a pharmaceutically acceptable salt thereof, wherein: each R¹ is,independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH, CF₃, or CN; each R²is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where eachn is, independently, 1 to 4; a compound of Formula XIV:

or a pharmaceutically acceptable salt thereof, wherein: D is

each B is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4,

and each X is, independently, O or S; a compound of Formula XV:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H or C₁₋₁₀alkyl; R² is H or C_(1-no) alkyl; and m is 1 or 2; a compound of FormulaXVI:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H or C₁₋₈alkyl; and R² is H or C₁₋₈ alkyl; a compound of Formula XVII:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H or C₁₋₈alkyl; and R² is H or C₁₋₈ alkyl; a compound of Formula XVIII:R¹-[-X-A₁-Y—X-A₂-Y-]_(m)—R²  XVIII or a pharmaceutically acceptable saltthereof, wherein: each X is, independently, NR⁸, —N(R⁸)N(R⁸)—, O, or S;each Y is, independently, C═O, C═S, O═S═O, —C(═O)C(═O)—, or—CR^(a)R^(b)—; R^(a) and R^(b) are each, independently, hydrogen, a PLgroup, or an NPL group; each R⁸ is, independently, hydrogen or alkyl; A₁and A₂ are each, independently, optionally substituted arylene oroptionally substituted heteroarylene, wherein A₁ and A₂ are,independently, optionally substituted with one or more PL group(s), oneor more NPL group(s), or a combination of one or more PL group(s) andone or more NPL group(s); or each A₁ is, independently, optionallysubstituted arylene or optionally substituted heteroarylene, and each A₂is a C₃ to C₈ cycloalkyl or —(CH₂)_(q)—, wherein q is 1 to 7, wherein A₁and A₂ are, independently, optionally substituted with one or more PLgroup(s), one or more NPL group(s), or a combination of one or more PLgroup(s) and one or more NPL group(s); or each A₂ is optionallysubstituted arylene or optionally substituted heteroarylene, and each A₁is a C₃ to C₈ cycloalkyl or —(CH₂)_(q)—, wherein q is 1 to 7, wherein A₁and A₂ are each, independently, optionally substituted with one or morePL group(s), one or more NPL group(s), or a combination of one or morePL group(s) and one or more NPL group(s); R¹ is hydrogen, a PL group, oran NPL group, and R^(e) is —X-A₁-Y—R¹¹, wherein R¹¹ is hydrogen, a PLgroup, or an NPL group; or R¹ and R² are each, independently, hydrogen,a PL group, or an NPL group; or R¹ and R² together are a single bond; orR¹ is —Y-A₂-X—R¹², wherein R¹² is hydrogen, a PL group, or an NPL group,and R² is hydrogen, a PL group, or an NPL group; each NPL group is,independently, —B(OR⁴)₂ or—(NR³)_(q1NPL)—U^(NPL)-LK^(NPL)—(NR^(3″))_(q2NPL)—R^(4′), wherein: R³,R^(3′), and R^(3″) are each, independently, hydrogen, alkyl, or alkoxy;R⁴ and R^(4′) are each, independently, hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, or heteroaryl, wherein each of the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more substitutents, wherein each substituent is,independently, alkyl, halo, or haloalkyl; each U^(NPL) is,independently, absent or O, S, S(═O), S(═O)₂, NR³, —C(═O)—, C(═O)—NR³—,—C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —S—C═N—, or —C(═O)—NR³—O—,wherein groups with two chemically nonequivalent termini can adopt bothpossible orientations; each LK^(NPL) is, independently, —(CH₂)_(pNPL)—or C₂₋₈ alkenylenyl, wherein each of the —(CH₂)_(pNPL) and C₂₋₈alkenylenyl is optionally substituted with one or more substituents,wherein each substituent is, independently, amino, hydroxyl, aminoalkyl,hydroxylalkyl, or alkyl; each pNPL is, independently, an integer from 0to 8; q1NPL and q2NPL are each, independently, 0, 1, or 2; each PL groupis, independently, halo, hydroxyethoxymethyl, methoxyethoxymethyl,polyoxyethylene, or —(NR^(5′))_(q1PL)—U^(PL)-LK^(PL)—(NR^(5″))_(q2PL)—V,wherein: R⁵, R^(5′), and R^(5″) are each, independently, hydrogen,alkyl, or alkoxy; each U^(PL) is, independently, absent or O, S, S(═O),S(═O)₂, NR⁵, —C(═O)—, —C(═O)—NR⁵—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—,—N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—, —C(═O)O—, —C(═O)S—, —C(═S)—,—O—P(═O)₂O—, —S—C═N—, or —C(═O)—NR⁵—O—, wherein groups with twochemically nonequivalent termini can adopt either of the two possibleorientations; each V is, independently, nitro, cyano, amino, halo,hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂wherein p is 1 to 5, —C(═O)NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—C(═O)NH(CH₂)_(p)NHC(═NH)NH₂ wherein p is 1 to 5,—C(═O)NH(CH₂)_(p)NHC(═O)NH₂ wherein p is 1 to 5, —NHC(═O)-alkyl,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, ureido, carbamoyl,—C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH,S(═O)₂OH, NR^(d)R^(e), semicarbazone, aryl, cycloalkyl,heterocycloalkyl, or heteroaryl, wherein each of the aryl and cycloalkylis substituted with one or more substitutents, wherein each of theheterocycloalkyl and heteroaryl is optionally substituted with one ormore substituents, and wherein each of the substituents for the aryl,cycloalkyl, heterocycloalkyl, and heteroaryl is, independently, nitro,cyano, amino, halo, hydroxy, alkoxy, alkylthio, alkylamino,dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂,diazamino, amidino, guanidino, ureido, carbamoyl, —C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH,NR^(d)R^(e), semicarbazone, aminosulfonyl, aminoalkoxy, aminoalkythio,lower acylamino, or benzyloxycarbonyl; each R^(c) is, independently,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl, each optionally substitutedby one or more substitutents, wherein each substituent is,independently, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl;R^(d) and R^(e) are, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl,wherein each of the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionallysubstituted by OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, orheterocycloalkyl; or R^(d) and R^(e) together with the N atom to whichthey are attached form a 4-, 5-, 6-, 7-, or 8-membered heterocycloalkyl;each LK^(PL) is, independently, —(CH₂)_(pPL)— or C₂₋₈ alkenylenyl,wherein each of the —(CH₂)_(pNPL)— and C₂₋₈ alkenylenyl is optionallysubstituted with one or more substituents, wherein each substituent is,independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;each pPL is, independently, an integer from 0-8; q1PL and q2PL are each,independently, 0, 1, or 2; and m is an integer from 1 to about 20;provided that the compound is not Compound X or Compound Y; a compoundof Formula XIX:R¹-[-X-A₁-X—Y-A₂-Y-]_(m)—R²  XIX or a pharmaceutically acceptable saltthereof, wherein: each X is, independently, NR⁸, O, S, —N(R⁸)N(R⁸)—,—N(R⁸)—(N═N)—, —(N═N)—N(R⁸)—, —C(R⁷R^(7′))NR⁸—, —C(R⁷R^(7′))O—, or—C(R⁷R^(7′))S—; each Y is, independently, C═O, C═S, O═S═O, —C(═O)C(═O)—,C(R⁶R^(6′))C═O, or C(R⁶R^(6′))C═S; each R⁸ is, independently, hydrogenor alkyl; each R⁷ and each R^(7′) are, independently, hydrogen or alkyl;or R⁷ and R^(7′) together form —(CH₂)_(p)—, wherein p is 4 to 8; each R⁶and each R^(6′) are, independently, hydrogen or alkyl; or R⁶ and R^(6′)together form —(CH₂)₂NR¹²(CH₂)₂—, wherein R¹² is hydrogen, —C(═N)CH₃, or—C(═NH)—NH₂; A₁ and A₂ are each, independently, optionally substitutedarylene or optionally substituted heteroarylene, wherein A₁ and A₂ areeach, independently, optionally substituted with one or more PLgroup(s), one or more NPL group(s), or a combination of one or more PLgroup(s) and one or more NPL group(s); or each A₂ is, independently,optionally substituted arylene or optionally substituted heteroarylene,and each A₁ is, independently, optionally substituted C₃ to C₈cycloalkyl, wherein A₁ and A₂ are each, independently, optionallysubstituted with one or more PL group(s), one or more NPL group(s), or acombination of one or more PL group(s) and one or more NPL group(s); R¹is hydrogen, a PL group, or an NPL group, and R² is —X-A₁-X—R¹, whereinA₁ is as defined above and is optionally substituted with one or more PLgroup(s), one or more NPL group(s), or a combination of one or more PLgroup(s) and one or more NPL group(s); or R¹ is hydrogen, a PL group, oran NPL group, and R² is —X-A′-X—R¹, wherein A′ is C₃ to C₈ cycloalkyl,aryl, or heteroaryl and is optionally substituted with one or more PLgroup(s), one or more NPL group(s), or a combination of one or more PLgroup(s) and one or more NPL group(s); or R¹ is —Y-A₂-Y—R², and each R²is, independently, hydrogen, a PL group, or an NPL group; or R¹ is —Y-A¹and R² is —X-A, wherein each A′ is, independently, C₃ to C₈ cycloalkyl,aryl, or heteroaryl and is optionally substituted with one or more PLgroup(s), one or more NPL group(s), or a combination of one or more PLgroup(s) and one or more NPL group(s); or R¹ and R² are, independently,a PL group or an NPL group; or R¹ and R² together form a single bond;each NPL is, independently, —B(OR⁴)₂ or—(NR^(3′))_(q1NPL)—U^(NPL)-LK^(NPL)—(NR^(3″))_(q2NPL)—^(4′), wherein:R³, R^(3′), and R^(3″) are each, independently, hydrogen, alkyl, oralkoxy; R⁴ and R^(4′) are each, independently, hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, and heteroaryl, wherein each of the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more alkyl or halo groups; each U^(NPL) is,independently, absent or O, S, S(═O), S(═O)₂, NR³, —C(═O)—, —C(═O)—NR³—,—C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —S—C═N—, or —C(═O)—NR³—O—,wherein groups with two chemically nonequivalent termini can adopt bothpossible orientations; each LK^(NPL) is, independently, —(CH₂)_(pNPL)—or C₂₋₈ alkenylenyl, wherein each of the —(CH₂)_(pNPL)— and C₂₋₈alkenylenyl is optionally substituted with one or more substituents,wherein each substituent is, independently, amino, hydroxyl, aminoalkyl,hydroxylalkyl, or alkyl; each pNPL is, independently, an integer from 0to 8; q1NPL and q2NPL are each, independently, 0, 1, or 2; each PL is,independently, halo, hydroxyethoxymethyl, methoxyethoxymethyl,polyoxyethylene, or —(NR^(5′))_(q1PL)—U^(PL)-LK^(PL)—(NR^(5′))_(q2PL)—V,wherein: R⁵, R^(5′), and R^(5″) are each, independently, hydrogen,alkyl, and alkoxy; each U^(PL) is, independently, absent or O, S, S(═O),S(═O)₂, NR⁵, —C(═O)—, —C(═O)—NR⁵—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—,—N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—, —C(═O)O—, —C(═O)S—, —C(═S)—,—O—P(═O)₂O—, —S—C═N—, or —C(═O)—NR⁵—O—, wherein groups with twochemically nonequivalent termini can adopt either of the two possibleorientations; each V is, independently, nitro, cyano, amino, halo,hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂wherein p is 1 to 5, —C(═O)NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—C(═O)NH(CH₂)_(p)NHC(═NH)NH₂ wherein p is 1 to 5,—C(═O)NH(CH₂)_(p)NHC(═O)NH₂ wherein p is 1 to 5, —NHC(═O)-alkyl,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, ureido, carbamoyl,—C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH,S(═O)₂OH, NR^(d)R^(e), semicarbazone, aryl, cycloalkyl,heterocycloalkyl, or heteroaryl, wherein each of the aryl and cycloalkylis substituted with one or more substitutents, wherein each of theheterocycloalkyl, and heteroaryl is optionally substituted with one ormore substituents, and wherein each of the substituents for the aryl,cycloalkyl, heterocycloalkyl, and heteroaryl is, independently, nitro,cyano, amino, halo, hydroxy, alkoxy, alkylthio, alkylamino,dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂,diazamino, amidino, guanidino, ureido, carbamoyl, —C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH,NR^(d)R^(e), semicarbazone, aminosulfonyl, aminoalkoxy, aminoalkythio,lower acylamino, or benzyloxycarbonyl; each LK^(PL) is, independently,—(CH₂)_(pPL)— or C₂₋₈ alkenylenyl, wherein each of the —(CH₂)_(pNPL)—and C₂₋₈ alkenylenyl is optionally substituted with one or moresubstituents, wherein each substituent is, independently, amino,hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl; each pPL is,independently, an integer from 0 to 8; q1PL and q2PL are each,independently, 0, 1, or 2; and m is an integer from 1 to about 20;provided that the compound is not Compound X or Compound Y; a compoundof Formula XIXa:R¹—X-A₁-X—Y-A₂-Y—X-A₁-X—R²  XIXa or pharmaceutically acceptable saltthereof, wherein: each X is, independently, NR⁸, O, S, or —N(R⁸)N(R⁸)—;each Y is, independently, C═O, C═S, or O═S═O; each R⁸ is, independently,hydrogen or alkyl; A₁ and A₂ are each, independently, optionallysubstituted arylene or optionally substituted heteroarylene, wherein A₁and A₂ are each, independently, optionally substituted with one or morePL group(s), one or more NPL group(s), or a combination of one or morePL group(s) and one or more NPL group(s); R¹ is a PL group or an NPLgroup; R² is R¹; each NPL is, independently,—(NR^(3′))_(q1NPL)—U^(NPL)-LK^(NPL)—(NR^(3″))_(q2NPL)—R^(4′), wherein:R³, R^(3′), and R^(3″) are each, independently, hydrogen, alkyl, oralkoxy; R⁴ and R^(4′) are each, independently, hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, or heteroaryl, wherein each of the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more alkyl or halo groups; U^(NPL) is,independently, absent or O, S, S(═O), S(═O)₂, NR³, —C(═O)—,—C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —S—C═N—, or —C(═O)—NR³—O—,wherein groups with two chemically nonequivalent termini can adopteither of the two possible orientations; each LK^(NPL) is,independently, —(CH₂)_(pNPL)— or C₂₋₈ alkenylenyl, wherein the—(CH₂)_(pNPL) is optionally substituted with one or more substituents,wherein each substituent is, independently, amino, hydroxyl, or alkyl;each pNPL is, independently, an integer from 0 to 8; q1NPL and q2NPL areeach, independently, 0, 1, or 2; each PL is, independently, halo,hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, or—(NR^(5′))_(q1PL)—U^(PL)-LK^(PL)—(NR^(5′))_(q2PL)—V, wherein: R⁵,R^(5′), and R^(5″) are each, independently, hydrogen, alkyl, or alkoxy;each U^(PL) is, independently, absent or O, S, S(═O), S(═O)₂, NR⁵,—C(═O)—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—,—C(═NR⁵)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—,—S—C═N—, or —C(═O)—NR⁵—O—, wherein groups with two chemicallynonequivalent termini can adopt both possible orientations; each V is,independently, nitro, cyano, amino, halo, hydroxy, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, ureido, carbamoyl,—C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH,S(═O)₂OH, NR^(d)R^(e), semicarbazone, aryl, heterocycloalkyl, orheteroaryl, wherein the aryl is substituted with one or moresubstitutents, wherein each of the heterocycloalkyl and heteroaryl isoptionally substituted with one or more substituents, and wherein eachof each of the substituents for the aryl, heterocycloalkyl, andheteroaryl is, independently, nitro, cyano, amino, halo, hydroxy,alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein pis 1 to 5, —N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, ureido,carbamoyl, —C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂,—NH—S(═O)₂OH, S(═O)₂OH, NR^(d)R^(e), semicarbazone, aminosulfonyl,aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl; eachLK^(PL) is, independently, —(CH₂)_(pPL)— or C₂₋₈ alkenylenyl, whereinthe —(CH₂)_(pNPL)— is optionally substituted with one or moresubstituents, wherein each substituent is, independently, amino,hydroxyl, or alkyl; each pPL is, independently, an integer from 0 to 8;and q1PL and q2PL are each, independently, 0, 1, or 2; provided that thecompound is not Compound X or Compound Y; a compound of Formula XX:

or a pharmaceutically acceptable salt thereof, wherein: each X is,independently, NR⁸; each Y is C═O; each R⁸ is, independently, hydrogenor alkyl; each A₂ is optionally substituted arylene or optionallysubstituted heteroarylene, and each A₁ is —(CH₂)_(q)—, wherein q is 1 to7, wherein A₁ and A₂ are each, independently, optionally substitutedwith one or more PL group(s), one or more NPL group(s), or a combinationof one or more PL group(s) and one or more NPL group(s); R² and R^(2a)are each, independently, hydrogen, a PL group, an NPL group or—X-A₁-Y—R¹¹, wherein R¹¹ is hydrogen, a PL group, or an NPL group; L¹ isC₁₋₁₀alkylene optionally substituted with one or more substitutents,wherein each substituent is, independently, alkyl, halo, haloalkyl,aminoalkyl, hydroxylalkyl, V, or —(CH₂)_(pPL)—V, wherein pPL is aninteger from 1 to 5; each NPL group is, independently, —B(OR⁴)₂ or—(NR^(3′))_(q1NPL)—U^(NPL)-LK^(NPL)—(NR^(3″))_(q2NPL)—R^(4′), wherein:R³, R^(3′), and R^(3″) are each, independently, hydrogen, alkyl, oralkoxy; R⁴ and R^(4′) are each, independently, hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, or heteroaryl, wherein each of the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more substitutents, wherein each substituent is,independently, alkyl, halo, or haloalkyl; each U^(NPL) is,independently, absent or O, S, S(═O), S(═O)₂, NR³, —C(═O)—, —C(═O)—NR³—,—C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —S—C═N—, or —C(═O)—NR³—O—,wherein groups with two chemically nonequivalent termini can adopt bothpossible orientations; each LK^(NPL) is, independently, —(CH₂)_(pNPL)—and C₂₋₈ alkenylenyl, wherein each of the —(CH₂)_(pNPL) and C₂₋₈alkenylenyl is optionally substituted with one or more substituents,wherein each substituent is, independently, amino, hydroxyl, aminoalkyl,hydroxylalkyl, or alkyl; each pNPL is, independently, an integer from 0to 8; q1NPL and q2NPL are each, independently, 0, 1, or 2; each PL groupis, independently, halo, hydroxyethoxymethyl, methoxyethoxymethyl,polyoxyethylene, or —(NR^(5′))_(q1PL)—U^(PL)-LK^(PL)—(NR⁵)_(q2PL)—V,wherein: R⁵, R^(5′), and R^(5″) are each, independently, hydrogen,alkyl, or alkoxy; each U^(PL) is, independently, absent or O, S, S(═O),S(═O)₂, NR⁵, —C(═O)—, —C(═O)—NR⁵—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—,—N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—, —C(═O)O—, —C(═O)S—, —C(═S)—,—O—P(═O)₂O—, —S—C═N—, or —C(═O)—NR⁵—O—, wherein groups with twochemically nonequivalent termini can adopt either of the two possibleorientations; each V is, independently, nitro, cyano, amino, halo,hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂wherein p is 1 to 5, —C(═O)NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—C(═O)NH(CH₂)_(p)NHC(═NH)NH₂ wherein p is 1 to 5,—C(═O)NH(CH₂)_(p)NHC(═O)NH₂ wherein p is 1 to 5, —NHC(═O)-alkyl,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, ureido, carbamoyl,—C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH,S(═O)₂OH, NR^(d)R^(e), semicarbazone, aryl, cycloalkyl,heterocycloalkyl, or heteroaryl, wherein each of the aryl and cycloalkylis substituted with one or more substitutents, wherein each of theheterocycloalkyl and heteroaryl is optionally substituted with one ormore substituents, and wherein each of the substituents for the aryl,cycloalkyl, heterocycloalkyl, and heteroaryl is, independently, nitro,cyano, amino, halo, hydroxy, alkoxy, alkylthio, alkylamino,dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂,diazamino, amidino, guanidino, ureido, carbamoyl, —C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH,NR^(d)R^(e), semicarbazone, aminosulfonyl, aminoalkoxy, aminoalkythio,lower acylamino, or benzyloxycarbonyl; each R^(c) is, independently,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl, each optionally substitutedby one or more substitutents, wherein each substituent is,independently, OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl;R^(d) and R^(e) are, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl,wherein each of the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionallysubstituted by OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, orheterocycloalkyl; or R^(d) and R^(e) together with the N atom to whichthey are attached form a 4-, 5-, 6-, 7-, or 8-membered heterocycloalkyl;each LK^(PL) is, independently, —(CH₂)_(pPL)— or C₂₋₈ alkenylenyl,wherein each of the —(CH₂)_(pNPL)— and C₂₋₈ alkenylenyl is optionallysubstituted with one or more substituents, wherein each substituent is,independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;each pPL is, independently, an integer from 0 to 8; q1PL and q2PL areeach, independently, 0, 1, or 2; m11 is an integer from 1 to about 20;and m12 is an integer from 1 to about 20; a compound of Formula XXI:R¹-[-X-A₁-Y—X-A₂-Y-]_(m13)—X-L¹-Y-[-X-A₁-Y—X-A₂-Y-]_(m14)—R²  XXI or apharmaceutically acceptable salt thereof, wherein: each X is,independently, NR⁸; each Y is C═O; each R⁸ is, independently, hydrogenor alkyl; each A₂ is optionally substituted arylene or optionallysubstituted heteroarylene, and each A₁ is —(CH₂)_(q)—, wherein q is 1 to7, wherein A₁ and A₂ are each, independently, optionally substitutedwith one or more PL group(s), one or more NPL group(s), or a combinationof one or more PL group(s) and one or more NPL group(s); R¹ is hydrogen,a PL group, or an NPL group, and R² is —X-A₁-Y—R¹¹, wherein R¹¹ ishydrogen, a PL group, or an NPL group; or R¹ and R² are each,independently, hydrogen, a PL group, or an NPL group; or R¹ and R²together are a single bond; or R¹ is —Y-A₂-X—R¹², wherein R¹² ishydrogen, a PL group, or an NPL group, and R² is hydrogen, a PL group,or an NPL group; L¹ is C₁₋₁₀alkylene optionally substituted with one ormore substitutents, wherein each substituent is, independently, alkyl,halo, haloalkyl, aminoalkyl, hydroxylalkyl, V, or —(CH₂)_(pPL)—V whereinpPL is an integer from 1 to 5; each V is, independently, hydroxy, amino,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—C(═O)NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —C(═O)NH(CH₂)_(p)NHC(═NH)NH₂wherein p is 1 to 5, —C(═O)NH(CH₂)_(p)NHC(═O)NH₂ wherein p is 1 to 5,—NHC(═O)-alkyl, —N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, carbamoyl,—C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH,S(═O)₂OH, NR^(d)R^(e), a substituted aryl group, heterocycloalkyl, orheteroaryl, wherein each of the heterocycloalkyl and heteroaryl isoptionally substituted with one more substituents, wherein eachsubstituent is, independently, amino, halo, cyano, nitro, hydroxy,—NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, amidino, guanidino,aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, orbenzyloxycarbonyl; and wherein the substituted aryl group is substitutedwith one more substituents, wherein each substituent is, independently,amino, halo, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,—N(CH₂CH₂NH₂)₂, amidino, guanidino, aminosulfonyl, aminoalkoxy,aminoalkythio, lower acylamino, or benzyloxycarbonyl; each NPL group is,independently, —B(OR⁴)₂ or—(NR³)_(q1NPL)—U^(NPL)-LK^(NPL)—(NR^(3″))_(q2NPL)—R^(4′), wherein: R³,R^(3′), and R^(3″) are each, independently, hydrogen, alkyl, or alkoxy;R⁴ and R^(4′) are each, independently, hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, or heteroaryl, wherein each of the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more substitutents, wherein each substituent is,independently, alkyl, halo, or haloalkyl; each U^(NPL) is,independently, absent or O, S, S(═O), S(═O)₂, NR³, —C(═O)—, —C(═O)—NR³—,—C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —S—C═N—, or —C(═O)—NR³—O—,wherein groups with two chemically nonequivalent termini can adopt bothpossible orientations; each LK^(NPL) is, independently, —(CH₂)_(pNPL)—or C₂₋₈ alkenylenyl, wherein each of the —(CH₂)_(pNPL) and C₂₋₈alkenylenyl is optionally substituted with one or more substituents,wherein each substituent is, independently, amino, hydroxyl, aminoalkyl,hydroxylalkyl, or alkyl; each pNPL is, independently, an integer from 0to 8; q1NPL and q2NPL are each, independently, 0, 1, or 2; each PL groupis, independently, halo, hydroxyethoxymethyl, methoxyethoxymethyl,polyoxyethylene, or —(NR^(5′))_(q1PL)—U^(PL)-LK^(PL)—(NR^(5″))_(q2PL)—V,wherein: R⁵, R^(5′), and R^(5″) are each, independently, hydrogen,alkyl, or alkoxy; each U^(PL) is, independently, absent or O, S, S(═O),S(═O)₂, NR⁵, —C(═O)—, —C(═O)—NR⁵—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—,—N═N—NR⁵—, —C(═N—N(R⁵)₂)—, C(═NR⁵)—, —C(═O)O—, —C(═O)S—, —C(═S)—,—O—P(═O)₂O—, —S—C═N—, or —C(═O)—NR⁵—O—, wherein groups with twochemically nonequivalent termini can adopt either of the two possibleorientations; each R^(e) is, independently, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, orheterocycloalkylalkyl, each optionally substituted by one or moresubstitutents, wherein each substituent is, independently, OH, amino,halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl, or heterocycloalkyl; R^(d) and R^(e) are,independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, wherein eachof the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted byOH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;or R^(d) and R^(e) together with the N atom to which they are attachedform a 4-, 5-, 6-, 7-, or 8-membered heterocycloalkyl; each LK^(PL) is,independently, —(CH₂)_(pPL)— or C₂₋₈ alkenylenyl, wherein each of the—(CH₂)_(pNPL)— and C₂₋₈ alkenylenyl is optionally substituted with oneor more substituents, wherein each substituent is, independently, amino,hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl; each pPL is,independently, an integer from 0 to 8; q1PL and q2PL are each,independently, 0, 1, or 2; m13 is an integer from 1 to about 10; and m14is an integer from 1 to about 10; a compound of Formula XXII:R¹-[-X-A₁-X—Z—Y-A₂-Y—Z]_(m)—R²  XXII or a pharmaceutically acceptablesalt thereof, wherein: X is NR⁸, —NR⁸NR⁸—, C═O, or O; Y is NR⁸,—NR⁸NR⁸—, C═O, S, or O; R⁸ is hydrogen or alkyl; Z is C═O, C═S, O═S═O,—NR⁸NR⁸—, or —C(═O)C(═O)—; A₁ and A₂ are, independently, optionallysubstituted arylene or optionally substituted heteroarylene, wherein A₁and A₂ are, independently, optionally substituted with one or more polar(PL) group(s), one or more non-polar (NPL) group(s), or a combination ofone or more polar (PL) group(s) and one or more non-polar (NPL)group(s); R¹ is (i) hydrogen, a polar group (PL), or a non-polar group(NPL), and R² is —X-A₁-X—R¹, wherein A₁ is as defined above and isoptionally substituted with one or more polar (PL) group(s), one or morenon-polar (NPL) group(s), or a combination of one or more polar (PL)group(s) and one or more non-polar (NPL) group(s); or (ii) hydrogen, apolar group (PL), or a non-polar group (NPL), and R² is—X-A₁-X—Z—Y-A₂-Y—R¹, wherein A₁ and A₂ are as defined above, and each ofwhich is optionally substituted with one or more polar (PL) group(s),one or more non-polar (NPL) group(s), or a combination of one or morepolar (PL) group(s) and one or more non-polar (NPL) group(s); or (iii)hydrogen, a polar group (PL), or a non-polar group (NPL), and R² is—X-A′-X—R¹, wherein A′ is aryl or heteroaryl and is optionallysubstituted with one or more polar (PL) group(s), one or more non-polar(NPL) group(s), or a combination of one or more polar (PL) group(s) andone or more non-polar (NPL) group(s); or (iv) hydrogen, a polar group(PL), or a non-polar group (NPL), and R² is —X-A₁-X—Z—Y-A′-Y—R¹, whereinA₁ is as defined above, A′ is aryl or heteroaryl, and each of A₁ and A′is optionally substituted with one or more polar (PL) group(s), one ormore non-polar (NPL) group(s), or a combination of one or more polar(PL) group(s) and one or more non-polar (NPL) group(s); or (v) —Z—Y-A¹and R² is hydrogen, a polar group (PL), or a non-polar group (NPL),wherein A′ is aryl or heteroaryl and is optionally substituted with oneor more polar (PL) group(s), one or more non-polar (NPL) group(s), or acombination of one or more polar (PL) group(s) and one or more non-polar(NPL) group(s); or (vi) —Z—Y-A′, and R² is —X-A″, wherein A′ and A″ are,independently, aryl or heteroaryl, and each of A and A″ is optionallysubstituted with one or more polar (PL) group(s), one or more non-polar(NPL) group(s), or a combination of one or more polar (PL) group(s) andone or more non-polar (NPL) group(s); or (vii) R¹ and R² are,independently, a polar group (PL) or a non-polar group (NPL); or (viii)R¹ and R² together form a single bond; NPL is a nonpolar groupindependently selected from —B(OR⁴)₂ and—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R^(4′),wherein: R³, R^(3′), and R^(3″) are, independently, selected fromhydrogen, alkyl, and alkoxy; R⁴ and R^(4′) are, independently, selectedfrom hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, andheteroaryl, any of which is optionally substituted with one or morealkyl or halo groups; U^(NPL) is absent or selected from O, S, S(═O),S(═O)₂, NR³, —C(═O)—, —C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—,—C(═N—N(R³)₂)—, —C(═NR³)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—,—R³⁰—, —R³S—, —S—C═N—, and —C(═O)—NR³—O—, wherein groups with twochemically nonequivalent termini can adopt both possible orientations;the —(CH₂)_(pNPL)— alkylene chain is optionally substituted with one ormore amino or hydroxy groups, or is unsaturated; pNPL is 0 to 8; q1NPLand q2NPL are, independently, 0, 1, or 2; PL is a polar group selectedfrom halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene,and —(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)(NR^(5′))_(q2PL)—V, wherein: R⁵,R^(5′), and R^(5″) are, independently, selected from hydrogen, alkyl,and alkoxy; U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵,—C(═O)—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—,—C(═NR⁵)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—,—S—C═N—, and —C(═O)—NR⁵—O—, wherein groups with two chemicallynonequivalent termini can adopt both possible orientations; V isselected from nitro, cyano, amino, hydroxy, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 4,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, guanyl, semicarbazone,aryl, heterocycle, and heteroaryl, any of which is optionallysubstituted with one or more of amino, halo, cyano, nitro, hydroxy,—NH(CH₂)_(p)NH₂ wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, amidino, guanidino,guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, orbenzyloxycarbonyl; the —(CH₂)_(pPL)— alkylene chain is optionallysubstituted with one or more amino or hydroxy groups, or is unsaturated;pPL is 0 to 8; q1PL and q2PL are, independently, 0, 1, or 2; and m is 1to about 20; a compound of Formula XXIII:R¹-[-A₁-W-A₂-W-]_(m)—R²  XXIII or a pharmaceutically acceptable saltthereof, wherein: A₁ and A₂ are, independently, optionally substitutedarylene or optionally substituted heteroarylene, wherein: (i) A₁ and A₂are, independently, optionally substituted with one or more polar (PL)group(s), one or more non-polar (NPL) group(s), or a combination of oneor more polar (PL) group(s) and one or more non-polar (NPL) group(s); or(ii) one of A₁ or A₂ is as defined above and is optionally substitutedwith one or more polar (PL) group(s), one or more non-polar (NPL)group(s), or a combination of one or more polar (PL) group(s) and one ormore non-polar (NPL) group(s); and the other of A₁ or A₂ is the group—C≡C(CH₂)_(p)C≡C—, wherein p is 0 to 8, and the —(CH₂)_(p)— alkylenechain is optionally substituted with one or more amino or hydroxylgroups; W is absent, or represents —CH₂—, —CH₂—CH₂—, —CH═CH—, or —C≡C—;R¹ is (i) hydrogen, a polar group (PL), or a non-polar group (NPL), andR² is -A₁-R¹, wherein A₁ is as defined above and is optionallysubstituted with one or more polar (PL) group(s), one or more non-polar(NPL) group(s), or a combination of one or more polar (PL) group(s) andone or more non-polar (NPL) group(s); or (ii) hydrogen, a polar group(PL), or a non-polar group (NPL), and R² is -A₁-W-A₂-R¹, wherein each ofA₁ and A₂ is as defined above and is optionally substituted with one ormore polar (PL) group(s), one or more non-polar (NPL) group(s), or acombination of one or more polar (PL) group(s) and one or more non-polar(NPL) group(s); or (iii) A′-W— and R² is -A₁-W-A′, wherein A′ is aryl orheteroaryl, either of which is optionally substituted with one or morepolar (PL) group(s), one or more non-polar (NPL) group(s), or acombination of one or more polar (PL) group(s) and one or more non-polar(NPL) group(s); or (iv) A′-W— and R² is -A′, wherein A′ is aryl orheteroaryl, either of which is optionally substituted with one or morepolar (PL) group(s), one or more non-polar (NPL) groups(s), or acombination of one or more polar (PL) group(s) and one or more non-polar(NPL) group(s); or (iv) R¹ and R² together form a single bond; NPL is anonpolar group independently selected from —B(OR⁴)₂ or—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R⁴, wherein:R³, R^(3′), and R^(3″) are, independently, selected from hydrogen,alkyl, and alkoxy; R⁴ is selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionallysubstituted with one or more alkyl or halo groups; U^(NPL) is absent orselected from O, S, S(═O), S(═O)₂, NR³, —(C═O)—, —(C═O)—N═N—NR³—,—(C═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—, —C(═O)O—,—C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³⁰—, —R³S—, —S—C═N— and —(C═O)—NR³—O—,wherein groups with two chemically nonequivalent termini can adopt bothpossible orientations; the —(CH₂)_(pNPL)— alkylene chain is optionallysubstituted with one or more alkyl, amino or hydroxyl groups, or thealkylene chain is unsaturated; pNPL is 0 to 8; q1NPL and q2NPL are,independently, 0 to 2; PL is a polar group selected from halo,hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5′))_(q2PL)—V, wherein: R⁵,R^(5′), and R^(5″) are, independently, selected from hydrogen, alkyl,and alkoxy; U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵,—(C═O)—, —(C═O)—N═N—NR⁵—, —(C═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—,—C(═NR⁵)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵O—, —R⁵S—,—S—C═N—, and —(C═O)—NR⁵—O—, wherein groups with two chemicallynonequivalent termini can adopt both possible orientations; V isselected from nitro, cyano, amino, hydroxyl, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂, —N(CH₂CH₂NH₂)₂, diazamino,amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle, andheteroaryl, any of which is optionally substituted with one or more ofamino, halo, cyano, nitro, hydroxyl, —NH(CH₂)_(p)NH₂, —N(CH₂CH₂NH₂)₂,amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio,lower acylamino, or benzyloxycarbonyl; the —(CH₂)_(pPL)— alkylene chainis optionally substituted with one or more amino or hydroxyl groups, orthe alkylene chain is unsaturated; pPL is 0 to 8; q1PL and q2PL are,independently, 0 to 2; and m is 1 to about 25; a compound of FormulaXIV:R¹—X-A₁-X—Y-A₂-Y—X-A₁-X—R²  XIV or a pharmaceutically acceptable saltthereof, wherein: X is NR⁸, O, S, or —N(R⁸)N(R⁸)—; Y is C═O, C═S, orO═S═O; R⁸ is hydrogen or alkyl; A₁ and A₂ are, independently, optionallysubstituted arylene or optionally substituted heteroarylene, wherein A₁and A₂ are, independently, optionally substituted with one or more polar(PL) group(s), one or more non-polar (NPL) group(s), or a combination ofone or more polar (PL) group(s) and one or more non-polar (NPL)group(s); R¹ is a polar group (PL) or a non-polar group (NPL); R² is R¹;NPL is a nonpolar group independently selected from —B(OR⁴)₂ and—(NR^(3′))_(q1NPL)—U^(NPL)—(CH₂)_(pNPL)—(NR^(3″))_(q2NPL)—R^(4′),wherein: R³, R^(3′), and R^(3″) are, independently, selected fromhydrogen, alkyl, and alkoxy; R⁴ and R^(4′) are, independently, selectedfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, and heteroaryl, any of which is optionally substitutedwith one or more alkyl or halo groups; U^(NPL) is absent or selectedfrom O, S, S(═O), S(═O)₂, NR³, —C(═O)—, —C(═O)—N═N—NR³—,—C(═O)—NR³—N═N—, —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—, —C(═O)O—,—C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R³O—, —R³S—, —S—C═N—, and—C(═O)—NR³—O—, wherein groups with two chemically nonequivalent terminican adopt both possible orientations; the —(CH₂)_(pNPL)— alkylene chainis optionally substituted with one or more amino or hydroxy groups, oris unsaturated; pNPL is 0 to 8; q1NPL and q2NPL are, independently, 0,1, or 2; PL is a polar group selected from halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, and—(NR^(5′))_(q1PL)—U^(PL)—(CH₂)_(pPL)—(NR^(5′))_(q2PL)—V, wherein: R⁵,R^(5′), and R^(5″) are, independently, selected from hydrogen, alkyl,and alkoxy; U^(PL) is absent or selected from O, S, S(═O), S(═O)₂, NR⁵,—C(═O)—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)₂)—,—C(═NR⁵)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —R⁵⁰—, —R⁵S—,—S—C═N—, and —C(═O)—NR⁵—O—, wherein groups with two chemicallynonequivalent termini can adopt both possible orientations; V isselected from nitro, cyano, amino, hydroxy, alkoxy, alkylthio,alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 4,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, guanyl, semicarbazone,aryl, heterocycle and heteroaryl, any of which is optionally substitutedwith one or more of amino, halo, cyano, nitro, hydroxy, —NH(CH₂)_(p)NH₂wherein p is 1 to 4, —N(CH₂CH₂NH₂)₂, amidino, guanidino, guanyl,aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, orbenzyloxycarbonyl; the —(CH₂)_(pPL)— alkylene chain is optionallysubstituted with one or more amino or hydroxy groups, or is unsaturated;pPL is 0 to 8; and q1PL and q2PL are, independently, 0, 1, or 2;provided that the compound is not Compound X or Compound Y; or acompound of Formula XV:A-(B)_(n1)-(D)_(m1)-H  XV or a pharmaceutically acceptable salt thereof,wherein: A is the residue of a chain transfer agent; B is—[CH₂—C(R¹¹)(B₁₁)]—, wherein B₁₁ is —X₁₁—Y₁₁—Z₁₁, wherein X₁₁ iscarbonyl (—C(═O)—) or optionally substituted C₁₋₆ alkylene; or X₁₁ isabsent; Y₁₁ is O, NH, or optionally substituted C₁₋₆ alkylene; or Y₁₁ isabsent; Z₁₁ is —Z_(11A)—Z_(11B), wherein Z_(11A) is alkylene, arylene,or heteroarylene, any of which is optionally substituted; or Z_(11B) isabsent; and Z_(11B) is -guanidino, -amidino, —N(R³)(R⁴), or—N⁺(R³)(R⁴)(R⁵), wherein R³, R⁴, and R⁵ are, independently, hydrogen,alkyl, aminoalkyl, aryl, heteroaryl, heterocyclic, or aralkyl; or Z₁₁ ispyridinium

or phosphonium

wherein R⁸¹, R⁹¹¹, R⁹²¹, and R⁹³¹ are, independently, hydrogen or alkyl;R¹¹ is hydrogen or C₁₋₄ alkyl; D is —[CH₂—C(R²¹)(D₂₁)]—, wherein D₂₁ is—X₂₁—Y₂₁—Z₂₁, wherein X₂₁ is carbonyl (—C(═O)—) or optionallysubstituted C₁₋₆ alkylene; or X₂₁ is absent; Y₂₁ is O, NH, or optionallysubstituted C₁₋₆ alkylene, or Y₂₁ is absent; Z₂₁ is alkyl, cycloalkyl,alkoxy, aryl, or aralkyl, any of which is optionally substituted; R²¹ ishydrogen or C₁₋₄ alkyl; m₁, the mole fraction of D, is about 0.1 toabout 0.9; and n₁, the mole fraction of B, is 1-m₁; wherein the compoundis a random copolymer of B and D, and wherein the copolymer has a degreeof polymerization of about 5 to about 50.